ES2390188T3 - Antiviral Nucleoside Analogs - Google Patents

Abstract

Compound of formula I: ** Formula ** in which: R is ORa, SRa, NRaRb, NRaNRbRc, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl substituted, aryl, substituted aryl, (CH2) n-CH ( NHR3) CO2Rb, (CH2) nS-alkyl, (CH2) nS-aryl, Cl, F, Br, I, CN, COORa, CONRaRb, NHC (> = NRa) NHRb, NRaORb, NRaNO, NHCONHRa, NRaN> = NRb , NRaN> = CHRb, NRaC (O) NRbRc, NRaC (S) NRbRc, NRaC (O) ORb, CH> = N-ORa, NRaC (> = NH) NRbRc, NRaC (O) NRbNRcRd, OC (O) Ra , OC (O) -ORa, ONHC (O) O-alkyl, ONH-C (O) O-aryl, ONRaRb, SNRaRb, S-ONRaRb, CHO, C (> = S) NRaRb, nitro, C (> = NRa) ORb or SO2NRaRb; and R3 is H, CN, NO2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkyls, CH> = CF2, CH (> = NRa) ORb, CHO, CH> = CH-OCH3, NHCONH2, NHCSNH2, CONRaRb , CSNRaRb, CO2Ra, alkoxy, NH2, alkylamino, dialkylamino, halogen, (1,3-oxazol-2-yl), (1,3-oxazol-5-yl), (1,3-thiazol-2-yl) , (imidazol-2-yl), (2-oxo [1,3] dithiol-4-yl), (furan-2-yl), (2H [1,2,3] triazol-4-yl), C (> = NH) NH2, C (> = NH) NHOH, C (> = NOH) NH2, acyl, substituted acyl, ORa, C (> = NRa) Rb, CH> = NNRaRb, CH> = NORa, CH ( ORa) 2, B (ORa) 2, C-CC (> = O) NRaRb, (CH2) nS-alkyl, (CH2) nS-aryl, (CH2) nS (O) -alkyl, (CH2) nS (O ) -aryl, (CH2) nS (O2) -alkyl, (CH2) nS (O2) -aryl, (CH2) n-SO2NRaRb or (CH2) n-ORa; or R and R3 together with the atoms to which they bind can form uncycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; n is 0-5; R1 is H, NRaRb, Cl, F, ORa, SRa, NHCORa, NHSO2Ra, NHCONHRa, CN, alkyl, aryl, ONRaRb or NRaC (O) ORb; R2 is a nucleoside sugar group; Ra, Rb, Rc and Rd are independently selected from the constituted group by H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2-alkyl, amino, substituted amino and NO; or Ra and Rb together with the nitrogen to which a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino ring bind; or Rb and Rc together with the nitrogen to which they are attached form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino ring; and Rc and Rd are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl , aryl, substituted aryl, heteroaryl and substituted heteroaryl; or Rc and Rd together with the N-atom to which they are attached can form a heterocycloalkyl, substituted heterocycloalkyl, substituted heteroaryl or heteroaryl; or a pharmaceutically acceptable salt thereof, for use in the treatment of a viral infection in an animal.

Description

Antiviral nucleoside analogs.

Background of the invention

Viral diseases are a leading cause of death and economic losses in the world.

The Flaviviridae family of viruses consists of three genera: flaviviruses (which include dengue, West Nile and yellow fever viruses), hepatitis virus (HCV) and pestiviruses (which include viral diarrhea virus bovine, VDVB). Diseases and pathological conditions caused by members of this family include yellow fever, dengue fever, Japanese encephalitis, St. Louis encephalitis, hepatitis B and C, West Nile disease and AIDS. Currently, infections caused by human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV) are responsible for the highest number of virus-related deaths worldwide. Although there are some drugs useful for treating HIV, there are only some drugs useful for treating HBV, and there are no drugs that are generally useful for treating HCV.

Ribavirin (1-β-D-ribofuranosyl-1-1,2,4-triazol-3-carboxamide) is a broad-spectrum antiviral nucleoside that does not induce synthetic interferon. Ribavirin is structurally similar to guanosine and exhibits in vitro activity against several DNA and RNA viruses including Flaviviridae (Davis. Gastroenterology 118: S104-S114, 2000). Ribavirin reduces serum levels of amino transferase to normal levels in 40% of patients, but does not decrease serum levels of HCV RNA (Davis. Gastroenterology 118: S104-S114, 2000). Therefore, ribavirin alone is not effective in reducing viral RNA levels. Additionally, ribavirin has significant toxicity and is known to induce anemia.

Interferons (IFN) are compounds that have been commercially available for the treatment of chronic hepatitis for almost a decade. IFNs are glycoproteins produced by immune cells in response to viral infection. IFNs inhibit viral replication of many viruses, including HCV. When used as a sole treatment for hepatitis C infection, IFN suppresses serum HCV RNA to undetectable levels. Additionally, IFN normalizes serum amino transferase levels. Unfortunately, the effects of IFN are temporary and only a sustained response occurs in 8% -9% of patients chronically infected with HCV (Davis. Gastroenterology 118: S104-S114, 2000).

HCV is a single stranded positive strand RNA virus with a well-characterized RNA-dependent RNA polymerase (RdRp) and a well-characterized disease evolution. HCV has infected approximately 170 million people worldwide, leading to a major health crisis as a result of the disease. In fact, over the next few years, the number of deaths from hepatocellular carcinoma and HCV-related liver disease may exceed those caused by AIDS. Egypt is the most affected country in the world, with an estimated 23% of the population carrying the virus; while in the US It has recently been determined that the prevalence of chronic infections is approximately 1.87% (2.7 million people). HCV infections become chronic in approximately 50% of cases. Of these, approximately 20% develop liver cirrhosis that can lead to liver failure, including hepatocellular carcinoma.

The NS5B region of HCV codes for a 65 KDa RdRp that is believed to be responsible for viral genome replication. The RdRp function as a catalytic subunit of the viral replicase required for the replication of all positive chain viruses. The NS5B protein has been well characterized, it has been shown that it has the conserved GDD motif of the RdRp and in vitro assay systems have been reported. Cellular location studies revealed that NS5B is associated with the membrane in the endoplasmic reticulum as well as NS5A, which suggests that these two proteins may remain associated with each other after proteolytic processing. Additional evidence suggests that NS3, NS4A and NS5B interact with each other to form a complex that functions as part of the HCV replication machinery.

The x-ray crystal structure of the NS5B apoenzyme has been determined and three very recent publications describe the unusual shape of the molecule. This unique shape for a polymerase, which resembles a flat sphere, is attributed to extensive interactions between the subdomains of the fingers and thumb so that the active site is completely surrounded, forming a cavity 15 Å wide and 20 Å deep . Modeling studies showed that the NS5B apoenzyme can adapt to the template-primer without large movement of the subdomains, suggesting that the structure is preserved during the polymerization reaction. It has been shown that RdRp polypeptides of various members of the Flaviviridae family and other viral families are conserved (J.A. Bruenn, Nucleic Acids Research, vol. 19, No. 2 p. 217, 1991).

Currently, there are no safe and effective therapeutic agents on the market that target HCV polymerase. There is currently a need for therapeutic agents and therapeutic procedures that are useful for treating viral infections, such as those caused by HCV, HIV and HBV.

S. A. Patil et al., Tetrahedron Letters, vol. 35, 1994, pages 5339-5342 disclose that the compound of formula

(12)

5 It is useful in the treatment of cancer.

Nishimura N et al: "Synthesis of pyrrolo [2,1-f] [1,2,4] triazine C-nucleosides. Isosteres of sangivamycin, tubercidin, and toyocamycin ”, CARBOHYDRATE RESEARCH, ELSEVIER SCIENTIFIC PUBLISHING COMPANY. AMSTERDAM,

10 NL, vol. 331, No. 1, March 9, 2001 (03/09/2001), pages 77-82, XP004317149, ISSN: 0008-6215) disclose pirrolo C-nucleotides [2,1-f] [1 , 2,4] triazine (compounds 7-9) for use against DNA and RNA viruses (page 77).

Summary of the invention

The present invention provides compounds that are inhibitors of viral RNA and DNA polymerases (for example hepatitis B virus polymerases, hepatitis C virus, human immunodeficiency virus, lapolium virus, Coxsackie virus A and B, rhinovirus , echovirus, smallpox virus, Ebola virus and West Nile virus) and which are useful for treating HCV, as well as other viral infections (for example flavivirales infections).

Accordingly, the invention provides a compound of formula I as described hereinbelow, or a pharmaceutically acceptable salt thereof, for use in the treatment of a viral infection in an animal (for example a human being. ).

25 Detailed Description of the Invention

Definitions

The term "pharmaceutically acceptable salt" as used herein refers to a compound.

30 of the present description derived from pharmaceutically acceptable bases, organic or inorganic acids. Examples of suitable acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic acids. , formic, benzoic, malonic, naphthalene-2-sulfonic, trifluoroacetic and benzenesulfonic. Salts derived from appropriate bases include, but are not limited to, alkalis such as sodium and ammonia.

The terms "treat", "treating" and "treatment" as used herein include administering a compound before the onset of clinical symptoms of a disease / pathological condition to prevent any symptoms, as well as administering a compound. after the onset of clinical symptoms of a disease / pathological condition to reduce or eliminate any symptoms, aspects or characteristics of the

40 disease / pathological state. It is not necessary that such a treatment be absolute to be useful.

The term "animal" as used herein refers to any animal, including mammals, such as, but not limited to, mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses. and primates In a specific embodiment of the invention the animal is a human being.

The term "therapeutically effective amount", in reference to treating a disease / pathological condition, refers to an amount of a compound, either alone or contained in a pharmaceutical composition that can have any detectable, positive effect on any symptom, aspect or characteristics of a disease / pathological state when administered as a single dose or in multiple doses. It is not necessary for an effect of this

50 type be absolute to be beneficial.

The term "alkyl" as used herein refers to alkyl groups having from 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl and the like. In a specific embodiment, the alkyl groups have 1

55 4 carbon atoms and are called lower alkyl.

The term "substituted alkyl" as used herein refers to an alkyl group having

from 1 to 3 substituents, said substituents being selected from the group consisting of alkoxy, alkoxyalkyl, tri (C1-C4 alkyl) silyl, substituted alkoxy, acyl, substituted acyl, acylamino, acyloxy, oxiacyl, amino, substituted amino, aminoacyl, aryl , substituted aryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro, N3, carboxyl, carboxyl esters, thiol, thioalkyl, substituted thioalkyl, thioaryl, substituted thioaryl, thioheteroaryl, thioheteroaryl, thiocycloalkyl, thiocycloalkyl, thiocycloalkyl, thiocycloalkyl, thiocycloalkyl, thiocycloalkyl, thiocyclohenylcycloalkyl substituted, cycloalkyl, substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic. In a specific embodiment of the invention, the term "substituted alkyl" refers to an alkyl group substituted with 1 to 3 substituents, said substituents being selected from the group consisting of alkoxy, alkoxyalkyl, tri (C1-C4 alkyl) silyl, acyl, acylamino, acyloxy, oxyacyl, amino, aminoacyl, aryl, aryloxy, cyano, halogen, hydroxyl, nitro, N3, carboxyl, carboxyl esters, thiol, thioalkyl, thioaryl, thioheteroaryl, thiocycloalkyl, thioheterocyclic heterocycloalkyl heterocyclic

The terms "alkenyl" or "alkene" as used herein refer to an alkenyl group having from 2 to 10 carbon atoms and having at least 1 alkenyl unsaturation site. Such groups are exemplified by vinyl (ethene-1-yl), allyl, but-3-en-1-yl and the like.

The term "substituted alkenyl" as used herein refers to alkenyl groups having from 1 to 3 substituents, said substituents being selected from those described above for a substituted alkyl.

The term "alkynyl" or "alkyne" as used herein refers to an alkynyl group having 2-10 carbon atoms and having at least 1 alkynyl unsaturation site. Such groups are exemplified by, but not limited to, ethin-1-yl, propin-1-yl, propin-2-yl, 1-methylprop-2-in-1-yl, butin-1-yl, butin- 2-yl, butin-3-yl and the like.

The term "substituted alkynyl" as used herein refers to alkynyl groups having from 1 to 3 substituents, said substituents being selected from those described above for a substituted alkyl.

The term "alkoxy" refers to the alkyl-O- group.

The term "substituted alkoxy" as used herein refers to the alkyl-O-substituted group.

The term "acyl" as used herein refers to the alkyl-C (O) -, alkenyl-C (O) -, alkynyl-C (O) -, cycloalkyl-C (O) -, aryl-C (O) -, heteroaryl-C (O) - and heterocyclic-C (O).

The term "substituted acyl" as used herein refers to the alkyl-C (O) - substituted, alkenyl-C (O) - substituted, alkynyl-C (O) - substituted, cycloalkyl-C ( O) - substituted, aryl-C (O) - substituted, heteroaryl-C (O) substituted and heterocyclic-C (O) - substituted.

The term "acylamino" as used herein refers to the C-group (O) NZ1Z2 in which each Z1 and Z2 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl , alkynyl and substituted alkynyl, and the substituents described above in the definition of substituted alkyl.

The term "acyloxy" as used herein refers to the groups alkyl-C (O) O-, alkyl-C (O) substituted, alkenyl-C (O) O-, alkenyl-C (O) O- substituted, alkynyl-C (O) O-, alkynyl-C (O) O- substituted, aryl-C (O) O-, aryl-C (O) O- substituted, cycloalkyl-C (O) O- , cycloalkyl-C (O) O-substituted, heteroaryl-C (O) O-, heteroaryl-C (O) O- substituted, heterocyclic-C (O) O- and heterocyclic-C (O) O-substituted.

The term "oxyacyl" as used herein refers to the alkyl-OC (O) -, substituted alkyl-OC (O), alkenyl-OC (O) -, alkenyl-OC (O) - substituted groups , alkynyl-OC (O) -, alkynyl-OC (O) - substituted, aryl-OC (O) -, arylOC (O) - substituted, cycloalkyl-OC (O) -, cycloalkyl-OC (O) - substituted, heteroaryl-OC (O) -, heteroaryl-OC (O) - substituted, heterocyclic-OC (O) - and heterocyclic-OC (O) - substituted.

The term "amino" as used herein refers to the group -NH2.

The term "substituted amino" as used herein refers to the group-NZ1Z2 in which Z1 and Z2 are as described above in the definition of acylamino, provided that Z1 and Z2 are not both hydrogen.

The term "aminoacyl" as used herein refers to the groups -NZ3C (O) alkyl, NZ3C (O) substituted alkyl, -NZ3C (O) cycloalkyl, -NZ3C (O) substituted cycloalkyl, -NZ3C ( O) alkenyl, NZ3C (O) substituted alkenyl, -NZ3C (O) alkynyl, -NZ3C (O) substituted alkynyl, -NZ3C (O) aryl, -NZ3C (O) substituted aryl, -NZ3C (O) heteroaryl, -NZ3C (O) substituted heteroaryl, -NZ3C (O) heterocyclic and -NZ3C (O) substituted heterocyclic, wherein Z3 is hydrogen or alkyl.

The term "aryl" as used herein refers to a monovalent aromatic cyclic group of from 6 to 14 carbon atoms having a single ring (for example, phenyl) or multiple condensed rings (for example, naphthyl or antrilo), condensed rings that may or may not be aromatic. The arils by way

Examples include, but are not limited to, phenyl and naphthyl.

The term "substituted aryl" as used herein refers to aryl groups that are substituted with from 1 to 3 substituents selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl, and the substituents described above. in the definition of substituted alkyl.

The term "aryloxy" as used herein refers to the aryl-O- group which includes, by way of example but not limited to, phenoxy, naphthoxy and the like.

The term "substituted aryloxy" as used herein refers to aryl-O-substituted groups. The term "carboxyl" as used herein refers to -COOH or salts thereof.

The term "carboxyl esters" as used herein refers to the groups -C (O) O-alkyl, C (O) O-substituted alkyl, -C (O) O-aryl and C (O) O-aryl substituted.

The term "cycloalkyl" as used herein refers to saturated or unsaturated cyclic hydrocarbon ring systems, such as those containing 1 to 3 rings and 3 to 7 carbons per ring. Exemplary groups include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and adamantyl.

The term "substituted cycloalkyl" as used herein refers to a cycloalkyl having from 1 to 5 substituents selected from the group consisting of oxo (= O), thioxo (= S), alkyl, substituted alkyl and the substituents described in the definition of substituted alkyl.

The term "cycloalkoxy" as used herein refers to -O-cycloalkyl groups.

The term "substituted cycloalkoxy" as used herein refers to substituted -O-cycloalkyl groups.

The term "formyl" as used herein refers to HC (O) -.

The term "halogen" as used herein refers to fluoro, chloro, bromo and iodo.

The term "heteroaryl" as used herein refers to an aromatic group of between 1 and 10.

40 carbon atoms and between 1 and 4 heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur in the ring. Heteroatom atoms of sulfur and nitrogen may also be present in their oxidized forms. Such heteroaryl groups may have a single ring (for example, pyridyl or furyl) or multiple condensed rings (for example, indolizinyl or benzothienyl) and may or may not be aromatic fused rings and / or contain a heteroatom. Exemplary heteroaryl groups include, but are not limited to,

Heteroaryls including pyridyl, pyrrolyl, thienyl, indolyl, thiophenyl and furyl.

The term "substituted heteroaryl" as used herein refers to heteroaryl groups that are substituted with from 1 to 3 substituents selected from the same group of substituents defined for substituted aryl.

The term "heteroaryloxy" as used herein refers to the group -O-heteroaryl.

The term "substituted heteroaryloxy" as used herein refers to the substituted -O-heteroaryl group.

The term "heterocycle" or "heterocyclic" or "heterocycloalkyl" refers to a saturated or unsaturated (but not heteroaryl) group having a single ring or multiple condensed rings, from 1 to 10 carbon atoms and from 1 to 4 heteroatoms selected from the group consisting of nitrogen, oxygen, sulfur, within the ring in which, in the condensed ring systems, one or more of the rings may be cycloalkyl, aryl or

Heteroaryl provided the point of attachment is through the heterocyclic ring. The sulfur and nitrogen heteroatoms may also be present in their oxidized forms.

The terms "substituted heterocycle" or "substituted heterocyclic" or "substituted heterocycloalkyl" refers to heterocycle groups that are substituted with from 1 to 3 of the same substituents defined for substituted aryl 65.

Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyl , quinoxaline, quinazoline, cinoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine,

5 piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4,5,6,7-tetrahydrobenzo [b] thiophene, thiazole, thiazolidine, thiophene, benzo [b] thiophene, morpholinyl, thiomorpholinyl (also called thiamorpholinyl ), piperidinyl, pyrrolidine, tetrahydrofuranyl and the like.

The term "heterocyclyloxy" as used herein refers to the group -O-heterocyclic.

The term "substituted heterocyclyloxy" as used herein refers to the substituted O-heterocyclic group.

The term "phosphate" as used herein refers to the groups -OP (O) (OH) 2 (monophosphate or

15 phospho), -OP (O) (OH) OP (O) (OH) 2 (diphosphate or diphospho) and -OP (O) (OH) OP (O) (OH) OP (O) (OH) 2 ( triphosphate or triphosphate) or salts thereof including partial salts thereof. It is understood that the initial oxygen of the mono, di and triphosphate may include the oxygen atom of a sugar.

The term "phosphate esters" as used herein refers to the mono, di and triphosphate groups described above in which one or more of the hydroxyl groups are substituted by an alkoxy group.

The term "phosphonate" refers to the groups -OP (O) (Z4) (OH) or -OP (O) (Z4) (OZ4) or salts thereof including partial salts thereof, in which each Z4 it is independently selected from hydrogen, alkyl, substituted alkyl, carboxylic acid and carboxylic ester. It is understood that the initial oxygen of the phosphonate may include the

25 oxygen of a sugar.

The term "thiol" as used herein refers to the group -SH.

The term "thioalkyl" or "alkylthioether" or "thioalkoxy" refers to the group -S-alkyl.

The term "substituted thioalkyl" or "substituted alkylthioether" or "substituted thioalkoxy" refers to the group -S-substituted alkyl.

The term "thiocycloalkyl" as used herein refers to the group -S-cycloalkyl.

The term "substituted thiocycloalkyl" as used herein refers to the group -S-substituted cycloalkyl.

The term "thioaryl" as used herein refers to the group -S-aryl. The term "substituted thioaryl" as used herein refers to the substituted S-aryl group.

The term "thioheteroaryl" as used herein refers to the group -S-heteroaryl.

The term "substituted thioheteroaryl" as used herein refers to the group -S-substituted heteroaryl.

The term "thioheterocyclic" as used herein refers to the group -S-heterocyclic.

The term "substituted thioheterocyclic" as used herein refers to the substituted -S-heterocyclic group.

The term "amino acid side chain" refers to the substituent Z7 of α-amino acids of the formula Z6NHCH (Z7) COOH in which Z7 is selected from the group consisting of hydrogen, alkyl, substituted alkyl

55 and aryl and Z6 is hydrogen or together with Z7 and the nitrogen and carbon atoms attached thereto respectively form a heterocyclic ring. In one embodiment, the α-amino acid side chain is the side chain of one of the twenty naturally occurring L amino acids.

The sugars described herein may be in the configuration either D or L. 60 Compounds of formula I

Compounds of the invention include compounds of formula I:

in which:

R 5 is ORa, SRa, NRaRb, NRaNRbRc, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH2) n-CH (NHRa) CO2Rb, (CH2) nS-alkyl, ( CH2) nS-aryl, Cl, F, Br, I, CN, COORa, CONRaRb, NHC (= NRa) NHRb, NRaORb, NRaNO, NHCONHRa, NRaN = NRb, NRaN = CHRb, NRaC (O) NRbRc, NRaC (S ) NRbRc, NRaC (O) ORb, CH = N-ORa, NRaC (= NH) NRbRc, NRaC (O) NRbNRcRd, OC (O) Ra, OC (O) -ORa, ONHC (O) O-alkyl, ONH -C (O) O-aryl; ONRaRb, SNRaRb, S-ONRaRb, CHO, C (= S) NRaRb, nitro, CH (NRa) ORb or

10 SO2NRaRb; and R3 is H, CN, NO2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH = CF2, CH (= NRa) ORb, CHO, CH = CH-OCH3, NHCONH2, NHCSNH2, CONRaRb, CSNRaRb , CO2Ra, alkoxy, NH2, alkylamino, dialkylamino, halogen, (1,3-oxazol-2-yl), (1,3-oxazol-5-yl), (1,3-thiazol-2-yl), ( imidazol-2-yl), (2-oxo [1,3] dithiol-4-yl), (furan-2-yl), (2H [1,2,3] triazol-4-yl), C (= NH) NH2, C (= NH) NHOH, C (= NOH) NH2, acyl, substituted acyl, ORa, C (= NRa) Rb, CH = NNRaRb, CH = NORa, CH (ORa) 2, B (ORa) 2, C = C

15 C (= O) NRaRb, (CH2) nS-alkyl, (CH2) nS-aryl, (CH2) nS (O) -alkyl, (CH2) nS (O) -aryl, (CH2) nS (O2) - alkyl, (CH2) nS (O2) -aryl, (CH2) n-SO2NRaRb or (CH2) n-ORa; or R and R3 together with the atoms to which they bind can form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;

20 n is 0-5;

R1 is H, NRaRb, Cl, F, ORa, SRa, NHCORa, NHSO2Ra, NHCONHRa, CN, alkyl, aryl, ONRaRb or NRaC (O) ORb;

R2 is a nucleoside sugar group;

Ra, Rb, Rc and Rd are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2- alkyl, amino, substituted amino and NO; or Ra and Rb together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino; or Rb and Rc along with the

The nitrogen to which they bind forms a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino; Y

Rc and Rd are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or Rc and Rd along with the

The N atom to which they bind can form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;

or a pharmaceutically acceptable salt thereof.

In an embodiment of the invention, the compounds of the invention include compounds of formula I:

in which:

R is ORa, SRa, NRaRb, NRaNRbRc, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH2) n-CH (NHRa) CO2Rb, (CH2) nS-alkyl, ( CH2) nS-aryl, Cl, F, Br, I, CN, COORa, CONRaRb, NHC (= NRa) NHRb, NRaORb, NRaNO, NHCONHRa, NRaN = NRb, NRaN = CHRb, NRaC (O) NRbRc, NRaC (S ) NRbRc, NRaC (O) ORb, CH = N-ORa, NRaC (= NH) NRbRc, NRaC (O) NRbNRcRd, OC (O) Ra, OC (O) -ORa, ONH

50 C (O) O-alkyl, ONH-C (O) O-aryl, ONRaRb, SNRaRb, S-ONRaRb, CHO, C (= S) NRaRb, nitro, CH (NRa) ORb or SO2NRaRb; and R3 is H, CN, NO2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH = CF2, CH (= NRa) ORb, CHO, CH = CH-OCH3, NHCONH2, NHCSNH2, CONRaRb, CSNRaRb , CO2Ra,

alkoxy, NH2, alkylamino, dialkylamino, halogen, (1,3-oxazol-2-yl), (1,3-oxazol-5-yl), (1,3-thiazol-2-yl), (imidazol-2 -yl), (2-oxo [1,3] dithiol-4-yl), (furan-2-yl), (2H [1,2,3] triazol-4-yl), C (= NH) NH2 , C (= NH) NHOH, C (= NOH) NH2, acyl, substituted acyl, ORa, C (= NRa) Rb, CH = NNRaRb, CH = NORa, CH (ORa) 2, B (ORa) 2, C = CC (= O) NRaRb or N (= NHNH2) NHNH2; or R and R3 together with the atoms to which they bind can form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;

n is 0-5;

R1 is H, NRaRb, Cl, F, ORa, SRa, NHCORa, NHSO2Ra, NHCONHRa, CN, alkyl, aryl, ONRaRb or NRaC (O) ORb;

R2 is a nucleoside sugar group;

Ra, Rb, Rc and Rd are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2-alkyl , amino, substituted amino and NO; or Ra and Rb together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino; or Rb and Rc together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino; Y

Rc and Rd are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or Rc and Rd together with the N atom to which they are attached can form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl;

or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound of formula I as described above, wherein R is ORa, Cl, SRa, NRaRb or NRaNRbRc; or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound of formula I as described above, wherein R is NRaRb; Ra is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2-alkyl and NO; and Rb is selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2-alkyl and NO; or Ra and Rb together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino.

In one embodiment, the invention provides a compound of formula I as described above, wherein R is NRaNRbRc, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, (CH2) n-CH (NHRa) CO2Rb, Cl, F, Br, I, CN, COORa, CONRaRb, NHC (= NRa) NHRb, NRaORb, NRaNO, NHCONHRa, NRaN = NRb, NRaN = CHRb, NRaC (O) NRbRc, NRaC (S) NRbRc, NRaC (O) ORb, CH = N-ORa, NRaC (= NH) NRbRc, NRaC (O) NRbNRcRd, OC (O) Ra, OC (O) -ORa, ONH-C (O) O -alkyl, ONH-C (O) O-aryl, ONRaRb, SNRaRb, S-ONRaRb or SO2NRaRb.

In one embodiment, the invention provides a compound of formula I as described above, wherein R1 is H or NRaRb; or a pharmaceutically acceptable salt thereof.

In one embodiment, the invention provides a compound of formula I as described above, wherein R2 is a nucleoside sugar group of group A, B, C, D, E; or F described later herein; or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound of formula I as described above, wherein R2 is ribose, 2-methylribose, 2-deoxyribose; 2-deoxy-2-fluororibose; arabinose; 2-deoxy2-fluoroarabinous; 2,3-dideoxyiribose; 2,3-dideoxy-2-fluoroarabinous; 2,3-dideoxy-3-fluororibose; 2,3-dideoxy-2,3dideshydroperibose; 2,3-dideoxy-3-azidorribose; 2,3-dideoxy-3-tiarribose; or 2,3-dideoxy-3-oxarribose; or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound of formula I as described above, wherein R2 is thioribibose, 2-deoxythioribibose; 2-deoxy-2-fluorothiorribose; thioarabinous; 2-deoxy-2fluorothioarabinous; 2,3-dideoxytrioribose; 2,3-dideoxy-2-fluorothioarabinous; 2,3-dideoxy-3-fluorothiorribose; 2,3-dideoxy-2,3-dideshydrotioribose; or 2,3-dideoxy-3-azidothiorribose; or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound of formula I as described above, wherein R2 is 4-hydroxymethylcyclopent-2-ene; 2,3-dihydroxy-4-hydroxymethylcyclopent-4-ene; 3-hydroxy-4-hydroxymethylcyclopentane; 2-hydroxy-4-hydroxymethylcyclopentene; 2-fluoro-3-hydroxy-4-hydroxymethylcyclopentane; 2,3-dihydroxy-4-hydroxymethyl-5-methylenecyclopentane; 4-hydroxymethylcyclopentane, 2,3-dihydroxy-4-hydroxymethylcyclopentane; or 2,3-dihydroxymethylcyclobutane; or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound of formula I as described above, wherein R2 is 4-hydroxymethylpyrrolidine; 2,3-dihydroxy-4-hydroxymethylpyrrolidine; 2/3-hydroxy-4-hydroxymethylpyrrolidine; 2-fluoro-3-hydroxy-4-hydroxymethylpyrrolidine; or 3-fluoro-2-hydroxy-4-hydroxymethylpyrrolidine; or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound of formula I as described above, wherein R3 is CN, NO2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, CH = CF2, CH (= NRa) ORb, CHO, CH = CH-OCH3, NHCONH2, NHCSNH2, CONRaRb, CSNRaRb, CO2Ra, alkoxy, NH2, alkylamino, dialkylamino, halogen, (1,3-oxazol-2-yl), (1,3 -oxazol-5-yl), (1,3-thiazol-2-yl), (imidazol-2-yl), (2-oxo [1,3] dithiol-4-yl), (furan-2-yl), (2H [1,2,3] triazol-4-yl), C (= NH) NH2, C (= NH) NHOH, C (= NOH) NH2, acyl, acyl

15 substituted, ORa, C (= NRa) Rb, CH = NNRaRb, CH = NORa, CH (ORa) 2, B (ORa) 2, C = CC (= O) NRaRb, (CH2) nS-alkyl, (CH2 ) nS-aryl, (CH2) nS (O) -alkyl, (CH2) nS (O) -aryl, (CH2) nS (O2) -alkyl, (CH2) nS (O2) -aryl, or (CH2) n -SO2NRaRb, (CH2) n-ORa.

In another embodiment, the invention provides a compound of formula I as described above, wherein R3 is CN, substituted alkyl, alkenyl, CONRaRb, CO2Ra, halogen or C (= NH) NH2.

In another embodiment, the invention provides a compound of formula I as described above, wherein R 3 is CN, hydroxymethyl, 1,2-dihydroxyethyl, vinyl, aminocarbonyl, methoxycarbonyl, carboxyl, fluoro, bromine or C (= NH) NH2.

In another embodiment, the invention provides a compound of formula I as described above, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of H, alkyl and substituted alkyl; or Ra and Rb together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino; or Rb and Rc together with the nitrogen to which they bind form a ring of

30 pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino.

In another embodiment, the invention provides a compound of formula I, which is a compound of the following formula (11);

or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a compound of formula I, which is a compound of the following formula (III);

or a pharmaceutically acceptable salt thereof; in which X is H or alkyl.

In one embodiment of the invention, "halogen" is Br, Cl or F. Nucleoside sugar groups 50 The term "nucleoside sugar group" as used herein includes cyclic groups and

acyclics that can be included as the sugar part of a nucleoside analogue of formula I. Many examples of such groups are known in the field of nucleoside chemistry (see for example Antiviral Drugs by John S. Driscoll (2002) published by Ashgate Publishing Ltd.).

5 The term "nucleoside sugar group" includes substituted and unsubstituted tetrahydrofuranyl and dihydrofuranyl compounds including those set forth in group (A) below, substituted and unsubstituted tetrahydrothiophenyl and dihydrothiophenyl compounds including those set forth in group (B) below. , substituted and unsubstituted alkyl compounds including those set forth in group (C) below, substituted and unsubstituted cycloalkyl and cycloalkenyl compounds including those set forth in group (D) below, compounds of

Substituted and unsubstituted dihydropyrrolidinyl and tetrahydropyrrolidinyl including those set forth in group (E) below, and substituted and unsubstituted dioxolane compounds, substituted and unsubstituted thioxolane and substituted and unsubstituted dithiolane including those exposed in group (F) a continuation.

Group A

Examples of substituted tetrahydro and dihydrofuranyl compounds include the compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

25 Group B

Examples of substituted tetrahydrothiophenyl and dihydrothiophenyl compounds include the compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

Group C

Examples of substituted alkyl compounds include compounds represented by:

Specific examples include, but are not limited to, the following compounds:

Group D

Examples of substituted cycloalkyl and cycloalkenyl compounds include the compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

Group E

Examples of substituted dihydropyrrolidinyl and tetrahydropyrrolidinyl compounds include the compounds represented by the general structures:

20 Specific examples include, but are not limited to, the following compounds:

Group F

Examples of compounds of substituted dioxolane, substituted thioxolane and substituted dithiolane include the compounds represented by the general structures:

Specific examples include, but are not limited to, the following compounds:

For structures in groups A-F, the following definitions apply:

R7 is H, OR14, N3, NH2 or F; and R’7 is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl; or R7 and R’7 together can be = CH2, = CHF; in which both R7 and R’7 are not OH; and when one of R7 and R’7 is NH2, the other is not OH; and when one of R7 and R’7 is N3, the other is not OH;

R8 is H, OR14, N3, NH2 or F; and R’8 is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl,

Alkynyl or substituted alkynyl; or R8 and R’8 together can be = CH2, = CHF; in which both R8 and R’8 are not OH; and when one of R8 and R’8 is NH2, the other is not OH; and when one of R8 and R’8 is N3, the other is not OH;

or R7 and R8 together can form

wherein: R100 is C1-12 alkyl, C3-8 cycloalkyl, aryl or heteroaryl; wherein any C1-12 alkyl and C3-8 cycloalkyl of R100 is unsubstituted or substituted with 1-3 substituents selected from halogen, hydroxyl, carboxyl and C1-4 alkoxy; and in which any aryl or heteroaryl of R100 is not

30 substituted or substituted with 1-5 substituents independently selected from R101;

each R101 is independently halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfonyl, cyano, nitro, amino, phenyl, carboxyl, trifluoromethyl, trifluoromethoxy, C1-4 alkylamino, di (C1- alkyl 4) amino, C1-4 alkanoyl, C1-4 alkanoyloxy or C1-4 alkyloxycarbonyl;

R9 is H, CH3, C2H5 or N3;

R’9 is CH2OR14, CH2F, CH2SH, CHFOH, CF2OH, CH2-diphosphate, CH2-triphosphate,

R10 and R11 are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl or (CH2) n-O- (CH2) mCH3;

R12 is an N-linked amino acid residue (for example -NH-CH (CH3) CO2alkyl or -NH-CH (isopropyl) -CO2alkyl); and R14 is H;

n is 2-5; Y m is 10-20.

In a specific embodiment of the invention for structures in groups A-F: R7 is H, OR14, N3, NH2 or F; and R’7 is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl or substituted alkynyl; or R7 and R’7 together can be = CH2, = CHF; in which both R7 and R’7 are not

OH; and when one of R7 and R’7 is NH2, the other is not OH; and when one of R7 and R’7 is N3, the other is not OH; R7 "is alkyl or substituted alkyl. R8 is H, OR14, N3, NH2 or F; and R’8 is H, F, OH, O-alkyl, alkyl, substituted alkyl, alkenyl, substituted alkenyl,

alkynyl or substituted alkynyl; or R8 and R’8 together can be = CH2, = CHF; in which both R8 and R’8 are not OH; and when one of R8 and R’8 is NH2, the other is not OH; and when one of R8 and R’8 is N3, the other is not OH; R9 is H, CH3, C2H5 or N3; R’9 is CH2OR14, CH2F, CH2SH, CHFOH, CF2OH,

R10 and R11 are each independently H, alkyl, aryl, substituted aryl, acyloxyalkyl or (CH2) n-O- (CH2) mCH3;

R12 is an N-linked amino acid residue (for example -NH-CH (CH3) CO2alkyl or -NH-CH (isopropyl) -CO2alkyl);

R13 is H, CH3, C2H5, CH2F, CH2OH, CH2CH2F, CH2CH2OH, CH2N3, CH2CH2N3, CH2NH2 or CH2CH2NH2;

R14 is H;

n is 2-5; Y

m is 10-20.

Isomers and physical forms

Those skilled in the art will appreciate that the compounds of the invention that have a chiral center can exist in and be isolated in optically active and racemic forms. Some compounds may show polymorphism. It is to be understood that the present invention encompasses any racemic, optically active, polymorphic, tautomeric or stereoisomeric form, or mixtures thereof, of a compound of the invention (for example a compound of formula I, which possesses the useful properties described in the The present report, being well known in the art how to prepare optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis or by chromatographic separation using a stationary phase chiral) and how to determine antiviral activity using the conventional tests described herein, or using other similar tests that are well known in the art.

An embodiment of the invention provides compounds that exhibit the absolute stereochemistry depicted in the examples hereinafter.

Pharmaceutical compositions, modes of administration and treatment procedures

The present description provides a compound of general formula I and a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound of general formula I as described herein. Such pharmaceutical compositions may also comprise a pharmaceutically acceptable carrier and other components known in the art, or may comprise only a compound of the general formula I.

Those skilled in the art are well aware of the pharmaceutically acceptable carriers described herein, including, but not limited to, vehicles, adjuvants, excipients or diluents. Normally, the pharmaceutically acceptable carrier is chemically inert to the active compounds and has no harmful side effects or toxicity in the conditions of use. Pharmaceutically acceptable carriers may include polymers and polymeric matrices.

The compounds described in the present description can be administered by any conventional method available for use in conjunction with pharmaceutical agents, either individual therapeutic agents or in combination with additional therapeutic agents.

The described compounds are administered in a pharmaceutically effective amount. The pharmaceutically effective amount of the compound and the dosage of the pharmaceutical composition administered will, of course, vary depending on known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration; the age, health and weight of the recipient; the severity and stage of the disease or the pathological state; the type of simultaneous treatment; the frequency of treatment; and the desired effect.

The daily dose of active substance can be expected to be approximately 0.001 to 1000 milligrams (mg) per kilogram (kg) of body weight per day. In one embodiment, the total amount is between about 0.1 mg / kg and about 100 mg / kg of body weight per day; in an alternative embodiment it is between about 1.1 mg / kg and about 50 mg / kg of body weight per day; Still in another alternative embodiment it is between 0.1 mg / kg and approximately 30 mg / kg body weight per day. The amounts described above can be administered as a series of smaller doses over a period of time if desired. The pharmaceutically effective amount can be calculated based on the weight of the original compound to be administered. If the salt shows activity by itself, the pharmaceutically effective amount can be estimated as before using the weight of the salt, or by other means known to those skilled in the art. The dosage of the active substance can be carried out in a different way than daily if desired.

The total amount of the compound administered will also be determined by the route, time and frequency of administration as well as by the existence, nature and extent of any adverse side effects that could accompany the administration of the compound and the desired physiological effect. One skilled in the art will appreciate that various diseases or pathological conditions, in particular chronic diseases or pathological conditions, may require prolonged treatment involving multiple administrations.

The pharmaceutical forms of the pharmaceutical compositions described herein (forms of the pharmaceutical compositions suitable for administration) contain from about 0.1 mg to about 3000 mg of active ingredient (i.e. the compounds disclosed) per unit. In these pharmaceutical compositions, the active ingredient will normally be present in an amount of about 0.5-95% by weight based on the total weight of the composition. Multiple pharmaceutical forms can be administered as part of a single treatment. The active ingredient can be administered to achieve peak plasma concentrations of the active ingredient of from about 0.2 to 70 = M, or from about 1.0 to 10 = M.

The active substance can be administered orally in solid pharmaceutical forms, such as capsules, tablets and powders, or in liquid pharmaceutical forms, such as elixirs, syrups and suspensions. It can also be administered parenterally, in sterile liquid pharmaceutical forms. The active substance can also be administered intranasally (nasal drops) or by inhalation through the pulmonary system, such as by propellant-based metered dose inhalers or dry powder inhalation devices. Other pharmaceutical forms such as transdermal administration, through patch or ointment mechanisms, are potentially possible.

Formulations suitable for oral administration may include (a) liquid solutions, such as a pharmaceutically effective amount of the compound dissolved in diluents, such as water, saline or orange juice; (b) capsules, sachets, tablets, lozenges and troches, each containing a predetermined pharmaceutically effective amount of the active ingredient, such as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, propylene glycol, glycerin and polyethylene alcohols,

either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent or emulsifying agent. The capsule forms may be of the usual type of hard or soft gelatin shell containing, for example, surfactants, lubricants and inert fillers, such as lactose, sucrose, calcium phosphate and corn starch. Tablet forms may include one or more of the following: lactose, sucrose, manito, corn starch, potato starch, alginic acid, microcrystalline cellulose, gum arabic, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc , magnesium stearate, calcium stearate, zinc stearate, stearic acid and other excipients, colorants, diluents, buffering agents, disintegrating agents, wetting agents, preservatives, flavoring agents and pharmacologically compatible carriers. The tablet forms for sucking may comprise the active ingredient in an aroma, usually sucrose and gum arabic or tragacanth, as well as tablets that buy the active ingredient in an inert base, such as gelatin and glycerin or sucrose and gum arabic, emulsions and gels which contain, in addition to the active principle, such carriers as is known in the art.

Formulations suitable for parenteral administration include sterile isotonic, aqueous and non-aqueous solutions for injection, which may contain antioxidants, buffers, bacteriostats and solutes that

convert the formulation into isotonic with the patient's blood, and sterile aqueous and non-aqueous suspensions that may include suspending agents, solubilizing agents, thickening agents, stabilizing agents and preservatives.

The compound can be administered in a physiologically acceptable diluent in a pharmaceutically acceptable carrier, such as a sterile liquid or a mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol or alcohol. hexadecyl, glycols, such as propylene glycol or polyethylene glycol such as polyethylene glycol 400, glycerol, ketals, such as 2,2-dimethyl-1,3-dioxolan-4-methanol, ethers, an oil, a fatty acid, a glyceride or fatty acid ester , an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methyl cellulose, hydroxypropyl methylcellulose or carboxymethyl cellulose,

or emulsifying agents and other pharmaceutical adjuvants.

Oils, which can be used in parenteral formulations, include petroleum, animal, vegetable oils

or synthetic Specific examples of oils include peanut, soy, sesame, cottonseed, corn, olive, petroleum jelly and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include salts of fatty acids and alkali metal, ammonium and triethanolamine, and suitable detergents include (a) cationic detergents such as, for example, dimethyldialkylammonium halides and alkylpyridinium halides, (b) detergents anionics such as, for example, alkyl-, aryl- and olefin-sulphonates, alkyl-, olefin-, ether- and monoglyceridesulfates and sulfosuccinates, (c) non-ionic detergents such as, for example, fatty amine oxides, acid alkanolamides fatty and copolymers of polyoxyethylene and polypropylene, (d) amphoteric detergents such as, for example, alkyl beta-aminopropionates and quaternary ammonium salts of 2-alkylimidazoline, and (e) mixtures thereof.

Parenteral formulations usually contain from about 0.5% to about 25% by weight of the active ingredient in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the injection site, such compositions may contain one or more nonionic surfactants that have a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant in such formulations It ranges from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.

Those skilled in the art also know pharmaceutically acceptable excipients well. The choice of excipient will be determined in part by the particular compound, as well as by the particular procedure used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following procedures and excipients are merely by way of example and by no means limiting. Pharmaceutically acceptable excipients preferably do not interfere with the action of the active ingredients and do not produce adverse side effects. Suitable carriers and excipients include solvents such as water, alcohol and propylene glycol, solid diluents and absorbents, surfactants, suspending agents, tablet preparation binders, lubricants, flavorings and coloring agents.

The compounds of the present invention, alone or in combination with other suitable components, can be prepared in aerosol formulations to be administered by inhalation. These aerosol formulations can be placed in pressurized acceptable propellants, such as dichlorodifluoromethane, propane and nitrogen. Such aerosol formulations can be administered by metered dose inhalers. They can also be formulated as pharmaceutical agents for non-pressurized preparations, such as in a nebulizer or an atomizer.

The formulations can be presented in sealed single dose or multiple dose containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) state that only requires the addition of the sterile liquid excipient, for example, water, for injections, immediately before use. Solutions and suspensions for improvised injection can be prepared from sterile powders, granules and tablets. Those of ordinary skill in the art are well aware of the requirements for pharmaceutically acceptable carriers effective for injectable compositions. See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Co., Philadelphia, Pa., Banker and Chalmers, Eds., 238-250 (1982) and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., 622-630 (1986).

Formulations suitable for topical administration include tablets comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and gum arabic, as well as creams, emulsions and gels which contain, in addition to the active principle, such carriers, such as Know in the matter. In addition, transdermal patches can be prepared using methods known in the art.

Additionally, formulations suitable for rectal administration may be presented as suppositories.

by mixing with a variety of bases such as emulsifying bases or water soluble bases. Formulations suitable for vaginal administration may be presented as vaginal ovules, buffers, creams, gels, pastes, foams or spray formulas containing, in addition to the active ingredient, such carriers known in the art that are appropriate.

One skilled in the art will appreciate that suitable procedures are available for administering a compound of the present invention to a patient and, although more than one route can be used to administer a particular compound, a particular route may provide a more immediate and more effective reaction. What other way.

Useful embodiments of pharmaceutical dosage forms for the administration of the compounds according to the present invention can be illustrated as follows.

A large number of hard cover capsules are prepared by filling two hard pieces of hard gelatin capsules each with 100 mg of active ingredient powder, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesium stearate.

A mixture of active ingredient in a digestible oil such as soybean oil, cottonseed oil or olive oil is prepared and injected by means of a positive displacement pump in molten gelatin to form soft gelatin capsules containing 100 mg of the active substance The capsules are washed and dried. The active substance can be dissolved in a mixture of polyethylene glycol, glycerin and sorbitol to prepare a mixture of water-miscible medicine.

A large number of tablets are prepared by conventional procedures such that the dosage unit is 100 mg of active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch and 98.8 mg lactose. Appropriate aqueous and non-aqueous coatings may be applied to increase palatability, improve elegance and stability or delay absorption.

The immediate-release tablets / capsules are solid oral pharmaceutical forms prepared by conventional and new methods. These units are taken orally without water for dissolution and immediate administration of the medication. The active substance is mixed in a liquid that contains a component such as sugar, gelatin, pectin and sweeteners. These liquids are solidified into oblong tablets or solid tablets by lyophilization and solid state extraction techniques. Pharmacological compounds can be compressed with sugars and polymers or effervescent viscoelastic and thermoplastic components to produce porous matrices intended for immediate release, without the need for water.

In addition, the compounds of the present invention can be administered in the form of nasal drops, or dosed amount and a nasal or oral inhaler. The drug is administered from a nasal solution as a fine spray or from a powder such as an aerosol.

The ability of a compound to inhibit viral polymerases can be evaluated using known assays. The ability of a compound to inhibit HCV NS5B polymerase can be evaluated using the following assay.

HCV NS5B polymerase assay

The antiviral activity of the test compounds (Okuse et al., Antiviral Res. 2005, 65, 23-34) in the cell line that replicates HCV RNA in a stable manner, AVA5, derived by transfection of the cell line was evaluated Human hepatoblastoma, Huh7 (Blight et al., Sci. 2000, 290, 1972). The compounds were added to the dividing cultures once a day for three days. Media was changed with each compound addition. The cultures generally began the test at a confluence of 30-50% and reached the confluence during the last day of treatment. Intracellular levels of HCV RNA and cytotoxicity were evaluated 24 hours after the last dose of compound.

Triplicate cultures were used to determine HCV RNA levels (in 48-well and 96-well plates) and cytotoxicity (in 96-well plates). A total of six untreated control cultures and triplicate cultures treated with α-interferon and ribavirin served as positive antiviral and toxicity controls.

Intracellular levels of HCV RNA were measured using a conventional transfer hybridization procedure in which HCV RNA levels are normalized to B-actin RNA levels in each individual culture (Okuse et al., Antivir. Res . 2005, 65, 23-34). Cytotoxicity was measured using a neutral red dye uptake assay (Korba and Gerin, Antivir. Res. 1992, 19, 55). HCV RNA levels in treated cultures are expressed as a percentage of the average levels of RNA detected in untreated cultures.

Representative compounds of formula I demonstrated significant activity in this assay.

Synthesis of the compound

The compound of formula I may be prepared using synthetic intermediates and synthetic procedures that are known, or may be prepared using the synthetic intermediates and synthetic procedures described herein, for example, as described in the following schemes.

The following abbreviations are used herein.

Tr: trityl Bn: benzyl TBDPS: tert-butyldiphenylsilyl m-CPBA: 3-chloroperoxybenzoic acid TFA: trifluoroacetic acid TBDMSCl: tert-butyldimethylsilyl chloride DMF: dimethylformamide THF: tetrahydrofuran LDA: diisopropylamine lithium chloride T-lithium ammonium chloride monomethoxytrityl MMTrCl: monomethoxytrityl DMAP chloride: dimethylaminopyridine DEAE: diethylaminoethyl-Sepharose CMA-80: Chloroform 80: MeOH 18: NH4OH: 2 CMA-50: Chloroform 50: MeOH 40: NH4OH: 10 Bz: benzoyl BnB benzyl BnB BHB: lithium hexamethyldisilazane TBDPSCI: tert-butyldiphenylsilyl chloride DMSO: dimethylsulfoxide RMgBr: alkylmagnesium bromide DIBAL: diisobutylaluminium hydride DBN: 1,5-diazabicyclo [4.3.0] non-5-ene DBU: 1,8-diazabicyclo [5.4. 0] undec-7-eno MeMgBr: methylmagnesium bromide

P: Represents a suitable protecting group

Scheme A-1.

Scheme A-2.

Compounds without 2’-C-methyl are prepared in the same manner as that provided in Scheme A-1 starting from ribonolactone or ribose with minor modifications.

Scheme A-3.

Compounds with S in the ring and with / without 2’-CH3 are prepared in the same manner as that provided in Scheme A-1 15 with minor modifications.

Scheme A-4.

Compounds with cyclopentane ring are prepared starting from suitably protected cyclopentanone derivatives.

10 Scheme A-5.

Compounds with pyrrolidine ring system are prepared by the following route.

The imine can be prepared using conventional procedures described in the literature.

Scheme A-6.

Compounds with alkyl side chain are also prepared in the same manner as that provided in Scheme A-1 starting from the corresponding aldehyde.

The compounds are prepared with modified ribose (such as 2-deoxyribose, 2-fluoro-2-deoxyribose, arabinose, 2,2'-difluoro-2-deoxyribose, 3-deoxyribose, 2,3-dideoxyribose, 2,3- dideoxydideshydroribribose, 4-azidorribose, etc.), tiarribose, pyrrolidine, cyclopentane ring systems from procedures well known in the literature and become the desired precursor with amino and cyano group in the pyrrole ring according to the scheme

15 A-1.

Scheme B-1.

The protective group (P) could be any suitable group that can be deprotected under normal conditions without affecting other groups in the molecule or the molecule itself.

Scheme B-2.

Compounds with R substituent are prepared in structure (I) by the following scheme. Some examples of the groups are provided in this scheme.

The removal of the "P" protecting groups provides compounds of the invention.

Scheme B-3.

Scheme B-4.

Scheme B-5.

Scheme B-6.

Compounds with substituent on R3 in structure (I) are prepared by the following schemes.

Scheme B-7.

Scheme B-8.

Scheme B-9.

Scheme B-10.

Scheme C-1.

Preparation of phosphates, phosphonates and triphosphates.

Scheme C-2.

15 B and R’7 are the same as in scheme C-1.

Scheme C-3.

Scheme E-1.

The invention will now be illustrated by the following examples.

Example 1

Hydrochloride of (2S, 3R, 4R, 5R) -2- (4-aminopyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran3,4 -diol (1k).

10 a. To a stirred solution of freshly distilled pyrrole (6.79 g, 100.89 mmol) in diethyl ether (100 ml) was added ethylmagnesium bromide (33.6 ml, 100.89 mmol, 3M solution in ether) slowly to 20 ° C The reaction mixture was further stirred at 20 ° C for 1 h and the solvent was removed in vacuo to give 1b. At 1b in dichloromethane (500 ml) at 0 ° C a solution of (3R, 4R, 5R) -3,4-bis (benzyloxy) -5- (benzyloxymethyl) -3-methyltetrahydrofuran-2-ol (1c, WO document was added 2006/050161, 10.96 g, 25.22 mmol) in dichloromethane (100 ml) and further stirred at 4 ° C

15 for 72 h. The reaction mixture was quenched by adding saturated ammonium chloride solution (200 ml) and the organic phase was separated. The aqueous phase was further extracted with dichloromethane (2 x 200 ml). The combined organic extracts were washed with water (2 x 50 ml) and brine (1 x 50 ml) and dried over MgSO4. After filtration, the filtrate containing 1d was treated with trifluoroacetic acid (4.14 g, 36.34 mmol) at 20 ° C and stirred for 14 h. The reaction mixture was washed with water (2 x 100 ml) and brine (1 x 50 ml) and dried (MgSO4). Behind the

filtration, the filtrate was concentrated to give 12.5 g of crude 1e.

NOTE: THF was also used to obtain the Grignard reagent instead of diethyl ether. THF was removed by distillation and traces by obtaining azeotrope with toluene.

b. Phosphorus oxychloride (19.33 g, 126.1 mmol) was added to N, N-dimethylformamide (100 ml) at 0 ° C and stirred for 30 min. To this solution 1e (12.1 g, 25.22 mmol) in dichloromethane (50 ml) was added slowly over a period of 15 min. at 0 ° C and stirring was continued for 1 h. The reaction mixture was quenched by adding saturated sodium acetate solution (100 ml) and stirred for 30 min. The reaction mixture was concentrated to remove dichloromethane and the residue was diluted with ethyl acetate (200 ml). The organic phase was separated and washed with water (2 x 100 ml) and brine (1 x 50 ml) and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was purified by flash chromatography using ethyl acetate in hexanes (0 to 12%) to give 2.92 g (22.6% of 1c) of 1f as a dark brown syrup. . MS (ES-): 510.2 (M-H) -.

NOTE: Only DMF was also used as solvent; there was no need for dichloromethane. For the final treatment, 2 N NaOH was used instead of sodium acetate.

C. To a stirred solution of 1f obtained above (2.5 g, 4.88 mmol) in tetrahydrofuran (50 ml) was added sodium hydride (0.39 g, 9.77 mmol, 60% dispersion in mineral oil) at 0 ° C After stirring for 30 min. at 0 ° C, O- (mesitylsulfonyl) hydroxylamine (1g, 1.15 g, 5.37 mmol, prepared by the Krause process, was added,

J.G. Synthesis, 1972, 140) at 0 ° C and stirred further for 2 h. The reaction mixture was quenched by adding water (20 ml) and extracted with ethyl acetate (2 x 50 ml). The combined organic extracts were washed with water (2 x 25 ml) and brine (1 x 25 ml) and dried (MgSO4). After filtration, the filtrate was concentrated to give 2.75 g of 1h as a dark syrup. MS (ES +): 527.43 (M + H) +.

Compound 1h can also be prepared as follows.

d.

Aldehyde 1f (5.2 kg, 10.16 moles) was dissolved in methyl tert-butyl ether (72.8 L) and loaded into a clean SS reactor (600 L). Aliquat 336 (0.25 kg, 0.61 mol) and ammonium chloride (6.53 kg, 122.07 mol) were added to the reactor and the reaction mixture was cooled to 0-5 ° C. Ammonium hydroxide (19.08 l, 137 mol, 28% solution in water) was added at 0-5 ° C followed by the addition of a solution of cold sodium hydroxide (0-5 ° C) (16.59 kg in 66 l of water, 414.75 moles) at the same temperature for a period of 3 h. The addition of sodium hypochlorite (251 L, 222.58 moles, 6% solution) was started at 0 ° C and during the addition the temperature was allowed to rise to 15 ° C. The reaction mixture was further stirred at RT for 2 h. The CCF showed the completion of the reaction. Ethyl acetate (104 L) was added to the reaction mixture and the phases were separated. The aqueous phase was reextracted with ethyl acetate (2 X 104 L). The combined organic phases were washed with water (52 L), sodium thiosulfate (2 X 156 L, 10% solution), water (52 L) and brine (70 L) and dried over sodium sulfate (10.4 kg) After filtration, the filtrate was concentrated in vacuo below 40 ° C to give the crude compound 1h (4.4 kg) as a dark syrup.

and.

To a stirred solution of 1h (2.56 g, 4.88 mmol) in dioxane (50 ml) was added water (15 ml) and cooled to 0 ° C. To this solution cooled to 0 ° C was added hydroxylamine-O-sulfonic acid (1.93 g, 17.10 mmol). After stirring for 1 h, a cold solution of potassium hydroxide (2.19 g, 39.0 mmol) in water and dioxane (20 ml + 20 ml) was added and further stirred at 0 ° C for 1 h. The reaction mixture was diluted with ethyl acetate (100 ml), the organic phase was separated and washed with water (2 x 50 ml) and brine (1 x 50 ml) and dried (MgSO4). After filtration, the filtrate was concentrated to give 2.6 g of 1i, which was used as is for the next step.

F.

To a stirred solution of 1i (2.55 g, 4.88 mmol) in N, N-dimethylacetamide (70 ml) was added formamidine acetate (5.08 g, 48.88 mmol) and the reaction mixture was stirred at 140 ° C for 3h. Most of the N, N-dimethylacetamide was removed in vacuo and the residue was suspended in water (100 ml), which was extracted with ethyl acetate (2 x 250 ml). The combined organic extracts were washed with water (50 ml) and brine (50 ml) and dried (MgSO4). After filtration, the filtrate was concentrated and the residue was purified by flash chromatography using a mixture of ethyl acetate and methanol (9: 1) in hexanes (0 to 30%) to provide impure compound (1.25 g). Further purification by silica gel chromatography gave 0.48 g (17.8% of 1f) of 1j, 7 - ((2S, 3S, 4R, 5R) -3.4bis (benzyloxy) -5- (benzyloxymethyl ) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2,4] triazin-4-amine, as a light brown solid. 1 H-NMR (CDCl 3): 5.87 (s, 1 H), 7.43-7.21 (m, 15 H), 6.88 (d, J = 4.5 Hz, 1 H), 6.50 ( d, J = 4.5 Hz, 1H), 5.87 (s, 1H), 5.36 (a, 2H, exchangeable D2O), 4.83 (dd, J = 31.8, 12.2 Hz, 2H), 4.68-4.52 (m, 4H), 4.40-4.35 (m, 1H), 4.04 (d, J = 8.8 Hz, 1H), 3.88 (dd , J = 10.9, 2.3 Hz, 1H), 3.69 (dd, J = 11.1, 3.6 Hz, 1H), 1.00 (s, 3H). MS (ES +): 551.40 (M + H) +.

NOTE: Acetic acid and n-BuOH can also be used as a solvent instead of dimethylacetamide.

g. To a stirred solution of 1j (0.27 g, 0.484 mmol) in dichloromethane (25 ml) was added boron trichloride (4.84 ml, 4.84 mmol, 1 M solution in dichloromethane) at -40 ° C and the mixture was stirred mix additionally at -40 ° C for 30 min. and slowly brought to 0 ° C in approximately 30 min. and stirred at 0 ° C for 20 min. The reaction was quenched by adding ethyl alcohol (50 ml) and concentrated under reduced pressure. Again, ethyl alcohol (50 ml) was added and concentrated. This operation was repeated 4 times. After concentration, the residue was dissolved in a mixture of isopropyl alcohol and methanol (20 and 2 ml) and methanol was removed by concentration in vacuo. The solid was separated, which was collected by filtration and dried at 60 ° C under vacuum to provide 39 mg (25%) of 1k, (2S, 3R, 4R, 5R) -2- (4-aminopyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran-3,4-diol, as a

5 colorless solid. 1H-NMR (DMSO-d6): 5 9.71 (sa, 1H, exchangeable D2O), 8.99 (sa, 1H, exchangeable D2O), 8.16 (s, 1H), 7.41 (d, J = 4.5 Hz, 1H), 6.97 (d, J = 4.7 Hz, 1H), 5.34 (s, 1H), 4.8-4.0 (m, 3H, exchangeable D2O), 3.81-3.56 (m, 4H), 0.79 (s, 3H). MS (ES +): 281.6 (M + H) +. Analysis: Calc. For C12H16N4O4. HCl: C, 45.50; H, 5.40; N, 17.68; Cl, 11.19; Found: C, 45.53; H, 5.54; N, 17.93; Cl, 11.17.

The compound 1k can also be prepared as follows.

h. To a solution of compound 1j (128 g) in methanol (1.4 L), conc. HCl was added. (130 ml) followed by 10% Pd / C (12 g) and the mixture was hydrogenated at 70 psi (483 kPa) for 10 h. Since the compound precipitated from the solution, water (500 ml) was added to the mixture and heated at 60 ° C for approximately 1 h and filtered through

15 of a layer of Celite. The Celite layer was resuspended with palladium in a mixture of water (400 ml) and methanol (400 ml) and heated at 60 ° C for approximately 1 h and filtered again through Celite. This operation was repeated until it was not composed undissolved. The combined filtrates were concentrated in vacuo and recrystallized from water and ethanol (1:20) to give 32.5 g of the desired product 1k as pale yellow crystals. The mother liquors were concentrated and recrystallized again giving another 5.6 g collection.

Example 2

25 (2S, 3R, 4R, 5R) -2- (4- (Dimethylamino) pyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran -3,4-diol (2e).

30 a. A solution of 1i (500 mg, 0.95 mmol, preparation given according to example 1) in EtOH (25 ml) was treated with conc. NH4OH. (28-30%, 9.5 ml) and hydrogen peroxide (30% in water, 0.3 ml) followed by stirring at RT for 20 h. Additional hydrogen peroxide (30% in water, 0.1 ml) was added and stirring was continued for 4 h. The reaction mixture was concentrated to dryness. The residue was treated with chloroform (50 ml) and washed with water (50 ml). The aqueous phase was extracted again with chloroform (50 ml). The combined extracts were washed with

Brine (50 ml), dried over MgSO4, filtered and concentrated to give a yellow syrup (2a, 0.51 g). MS (ES-): 540.1 (M-H) -. The crude product 2a (0.48 g) was dissolved in triethyl orthoformate (10 ml) and treated with TFA (0.07 ml, 0.91 mmol) followed by stirring at 80 ° C for 45 min. and concentration to dryness. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 1: 1) to give 2b (375 mg, 76% over 2 steps, Rf = 0.33, hexanes / EtOAc = 1: 0) as a light brown syrup. 1H-NMR (DMSO-d6): 5.11.70 (sa, 1H), 7.90 (d, J = 3.1 Hz, 1H), 7.43-7.20 (m, 15H), 6, 84 (d, J = 4.4 Hz, 1H), 6.67 (d, J = 4.4 Hz, 1H), 5.56 (s, 1H), 4.77

5 4.53 (m, 6H), 4.22-4.15 (m, 1H), 3.99 (d, J = 8.2 Hz, 1H), 3.85-3.65 (m, 2H ), 1.07 (s, 3H); MS (ES-): 550.6 (M-H) -.

b. A solution of 2b (3,413 g, 6.19 mmol) in acetonitrile (80 ml) was treated with benzyltriethylammonium chloride (2.88 g, 98%, 12.39 mmol) and N, N-dimethylaniline (1.2 ml , 9.37 mmol). The mixture was heated to 80 ° C and treated with phosphorus oxychloride (3.5 ml, 37.85 mol) followed by stirring at 80 ° C for 45 min. Additional phosphorus oxychloride (15 ml) was added and stirring was continued at 80 ° C for 2.5 h. The third portion of phosphorus oxychloride (10 ml) was added and stirring was continued at 80 ° C for another 3 h. The reaction mixture was concentrated to dryness. The residue was dissolved in chloroform (400 ml) and washed with 1 M NaHCO3 (200 ml), water (200 ml), brine (100 ml) and dried over MgSO4. After filtration, the filtrate was concentrated and purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 4: 1) to give 2c (2.67 g, 76%, Rf = 0.45,

15 hexanes / EtOAc = 4: 1) as a yellow oil. 1H-NMR (DMSO-d6): 8.49 (s, 1H), 7.44-7.22 (m, 16H), 7.07 (d, J = 4.7 Hz, 1H), 5, 74 (s, 1H), 4.79-4.55 (m, 6H), 4.29-4.21 (m, 1H), 4.05 (d, J = 8.0 Hz, 1H), 3 , 89-3.70 (m, 2H), 1.03 (s, 3H).

C. A solution of 2c (200 mg, 0.35 mmol) in EtOH (6 ml) and chloroform (1.5 ml) was treated with triethylamine (0.92 ml,

6.6 mmol) and then dimethylamine (40% in water, 0.44 ml, 3.51 mmol) followed by stirring at 50 ° C for 12 h. The reaction mixture was concentrated and purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 1: 1) to give 2d (189 mg, 93%, Rf = 0.42, hexanes / EtOAc = 1: 1) as a light yellow syrup. 1H-NMR (DMSO-d6): 5.87 (s, 1H), 7.42-7.25 (m, 15H), 6.91 (d, J = 4.6 Hz, 1H), 6, 78 (d, J = 4.6 Hz, 1H), 5.70 (s, 1H), 4,804.54 (m, 6H), 4.23-4.15 (m, 1H), 3.99 (d , J = 8.5 Hz, 1H), 3.87-3.67 (m, 2H), 3.36 (s, 6H), 1.03 (s, 3H); MS (ES +):

25 579.1 (M + H) +.

d. A solution of 2d (109 mg, 0.19 mmol) in MeOH (15 ml) was treated with 1 N HCl (0.69 ml aq.) And Pd / C (10%, 50 mg) followed by hydrogenation (60 psi) (414 kPa) for 20 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 1: 1) to give the

Desired compound, 2e (52 mg, 89%, Rf = 0.60, chloroform / CMA 80 = 1: 1) as a white solid. Mp: 181 ° C; 1H-NMR (DMSO-d6): 5 7.83 (s, 1H), 6.93 (d, J = 4.5 Hz, 1H), 6.77 (d, J = 4.5 Hz, 1H) , 5.42 (s, 1H), 4.89 (d, J = 7.0 Hz, 1H), 4.80 (t, J = 5.4 Hz, 1H), 4.70 (s, 1H) , 3.80-3.54 (m, 4H), 3.35 (s, 6H), 0.77 (s, 3H); MS (ES +): 309.5 (M + H) +; IR (KBr): 3477, 3382, 2913, 1593, 1559, 1416, 1054 cm-1. Anal. calc. for C14H20N4O4: C, 54.53; H, 6.54; N, 18.17. Found: C, 54.45; H, 6.72; N, 17.70.

Example 3

40 (2S, 3R, 4R, 5R) -2- (4-Amino-5-bromopyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3- methyltetrahydrofuran-3,4diol (3b).

45 a. A solution of 1j (100 mg, 0.18 mmol, preparation given according to example 1) in CH2Cl2 (9 ml) was cooled with ice / water bath and treated with NBS in several portions (32 mg, 0.18 mmol ) followed by stirring at RT for 1 h. The reaction mixture was concentrated and purified by silica gel column chromatography (chloroform / methanol, 1: 0 to 20: 1) to give 3a (102 mg, 90%, Rf = 0.53, chloroform / MeOH = 95: 5) as a yellow solid. 1H-NMR (DMSO-d6): 5.89 (s, 1H), 7.42-7.25 (m, 15H), 6.91 (s, 1H), 5.64 (s, 1H), 4.74 (s, 2H), 4.66-4.52

50 (m, 4H), 4.22-4.16 (m, 1H), 4.03 (d, J = 8.7 Hz, 1H), 3.90-3.68 (m, 2H), 1 , 05 (s, 3H); MS (ES +): 631.3 (M + H) +.

b. A solution of 3a (87 mg, 0.14 mmol) in dichloromethane (2.5 ml) was cooled to -78 ° C and treated with drop BCl3

dropwise (1 M in dichloromethane, 1.4 ml) followed by stirring at -78 ° C for 2 h and at -25 ° C for 2.5 h. The reaction mixture was treated with CH2Cl2 / MeOH (1: 1, 1.5 ml) and stirred at -15 ° C for 0.5 h. It was then neutralized with conc. NH4OH. at 0 ° C and stirred at room temperature for 15 min. Followed by vacuum concentration. The residue was treated with MeOH (25 ml) and 4M HCl in 1,4-dioxane (12.5 ml) and stirred at room temperature for 1 h 5 followed by concentration. The residue was purified on a silica gel column using chloroform: CMA 80 (of

1: 0 to 1: 1, Rf = 0.24, chloroform: CMA 80 = 1: 1) as eluent. It was further purified by HPLC (CH3CN / H2O, 0-40 min., 0-30% CH3CN, monitoring at 244 nm). Fractions containing the desired product, 3b (t R = 30.5 min.) Were concentrated to give a white solid (15.7 mg, yield: 31%, HPLC proven purity: 98.4%). 1H-NMR (DMSO-d6, D2O exchange): 5 7.85 (s, 1H), 6.94 (s, 1H), 5.36 (s, 1H), 3.78-3.50

10 (m, 4H), 0.79 (s, 3H); MS (ES-): 357.2 (M-H) -; IR (KBr): 3465, 1636, 1473, 1065 cm-1.

Example 4

(2S, 3R, 4R, 5R) -2- (4-Amino-5-vinylpyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran -3,4-diol (4f).

20 a. A suspension of 1k HCl (504 mg, 1.59 mmol) in DMF (15 ml) and acetone (15 ml) was treated with 2,2-dimethoxypropane (3.5 ml, 98%, 27.96 mmol) and p- TsOH (440 mg, 98.5%, 2.28 mmol) followed by stirring at RT for 5 h. The reaction mixture was neutralized with 2N NaOH (aq.) Followed by concentration to dryness. The residue was purified by silica gel column chromatography (chloroform / methanol, from 1: 0 to 95: 5) to give

4a (504 mg, 99%, Rf = 0.33, chloroform / methanol = 95: 5) as a yellow solid. 1H-NMR (DMSO-d6): 5.8.83 (s, 1H), 7.68 (sa, 2H), 6.87 (d, J = 4.6 Hz, 1H), 6.63 (d, J = 4.6 Hz, 1H), 5.54 (s, 1H), 4.97 (t, J = 5.8 Hz, 1H), 4.37 (d, J =

2.4 Hz, 1H), 4.03-3.96 (m, 1H), 3.65-3.50 (m, 2H), 1.55 (s, 3H), 1.33 (s, 3H ), 1.15 (s, 3H); MS (ES +): 321.2 (M + H) +.

b. A solution of 4a (467 mg, 1.46 mmol) in pyridine (14 ml) was treated with DMAP (46 mg, 99%, 0.37 mmol) and trityl chloride (630 mg, 2.21 mmol) followed by stirring at RT for 16 h. Additional trityl chloride 5 (900 mg, 3.16 mmol) was added and stirring was continued at RT for 70 h. The reaction mixture was diluted with EtOAc (200 ml) and washed with water (2 x 100 ml) and brine (100 ml), dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc / MeOH, from 1: 1: 0 to 1: 1: 0.1) to give 4b (682 mg, 83%, Rf = 0.48, hexanes / EtOAc / MeOH = 1: 1: 0.1) as a yellow oil. 1 H-NMR (DMSO-d6): 5. 7.83 (s, 1 H), 7.70 (s, 2 H), 7.50-7.24 (m, 15 H), 6.89 (d, J = 4 , 3 Hz, 1H), 6.55 (d, J = 4.3 Hz, 1H), 5.57

10 (s, 1H), 4.26 (d, J = 3.0 Hz, 1H), 4.20-4.12 (m, 1H), 3.23 (d, J = 5.2 Hz, 2H ), 1.54 (s, 3H), 1.31 (s, 3H), 1.08 (s, 3H); MS (ES +): 585.1 (M + Na) +.

C. A solution of 4b (606 g, 1.08 mmol) in CH2Cl2 (50 ml) was cooled with ice / water and treated with NBS in several portions (627 mg, 3.49 mmol) followed by stirring at RT for 1 h . The reaction mixture was concentrated and

15 purified by silica gel column chromatography (hexanes / EtOAc / MeOH, from 1: 1: 0 to 1: 1: 0.1) to give 4c (626 mg, 90%, Rf = 0.62, hexanes / EtOAc / MeOH = 1: 1: 0.1) as a white solid. 1H-NMR (DMSO-d6): 5.87 (s, 1H), 7.50-7.25 (m, 17H), 6.64 (s, 1H), 5.53 (s, 1H), 4.26 (d, J = 3.1 Hz, 1H), 4.23-4.16 (m, 1H), 3.23 (d, J = 5.5 Hz, 2H), 1.53 (s , 3H), 1.31 (s, 3H), 1.03 (s, 3H); MS (ES +): 663.1 (M + Na).

20 d. A solution of 4c (15.45 g, 24.08 mmol) in pyridine (260 ml) was treated with 4-methoxytriphenylmethyl chloride (38 g, 97%, 119.36 mmol) followed by stirring at 70 ° C for 37 h. The reaction mixture was diluted with EtOAc (800 ml) and washed with water (2 x 500 ml) and brine (300 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 8: 1) to give 4d (31 g, used as is for the next step, Rf = 0.56, hexanes / EtOAc = 4: 1) as a light yellow solid. 1 H-NMR (DMSO-d6):

25 5 7.94 (s, 1H), 7.63 (s, 1H), 7.50-7.16 (m, 27H), 6.89 (d, J = 9.0 Hz, 2H), 6 , 72 (s, 1H), 5.49 (s, 1H), 4.24 (d, J = 2.8 Hz, 1H), 4.22-4.14 (m, 1H), 3.73 ( s, 3H), 3.23 (d, J = 5.5 Hz, 2H), 1.49 (s, 3H), 1.28 (s, 3H), 1.05 (s, 3H); MS (ES +): 937.3 (M + Na) +.

and. A solution of 4d above (31 g from the previous step) in DME (500 ml) was treated with vinyltrifluoroborate.

30 potassium (7.8 g, 58.23 mmol), NaHCO3 (5.9 g, 70.23 mmol), Pd (PPH3) 2Cl2 (1.2 g, 98%, 1.68 mmol) and H2O (55 ml) followed by reflux for 6 h. The reaction mixture was treated with water (500 ml) and extracted with EtOAc (1.0 L and 0.5 L). The combined extracts were washed with brine (500 ml) and dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 8: 1) to give 4e (11.32 g, 55% over two stages, Rf = 0.22, hexanes / EtOAc = 8: 1) as a yellow solid. 1 H-NMR

35 (DMSO-d6): 5 7.54 (s, 1H), 7.48-7.20 (m, 28H), 7.13 (dd, J = 17.4, 11.0 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 6.76 (s, 1H), 5.55 (dd, J = 17.4, 1.4 Hz, 1H), 5.50 (s , 1H), 5.29 (dd, J = 11.0, 1.4 Hz, 1H), 4.24 (d, J = 3.0 Hz, 1H), 4.18-4.12 (m, 1H), 3.71 (s, 3H), 3.22 (d, J = 5.3 Hz, 2H), 1.48 (s, 3H), 1.27 (s, 3H), 1.07 ( s, 3H).

F. A solution of 4e (205 mg, 0.23 mmol) in acetonitrile (25 ml) was treated with 1 N HCl (aq. 2.5 ml) followed by

40 stirring at RT for 23 h. The reaction mixture was concentrated to dryness and purified by silica gel column chromatography (chloroform / CMA 80, 1: 0 to 1: 1) to give 4f (36 mg, 51%, Rf = 0.12, chloroform / CMA 80 = 1: 1) as a yellow solid. Mp: 128-131 ° C; 1H-NMR (DMSO-d6): 7.78 (s, 1H), 7.32 (s, 2H), 7.23 (dd, J = 16.9, 10.8 Hz, 1H), 7, 03 (s, 1H), 5.58 dd, J = 16.9, 1.5 Hz, 1H), 5.35 (s, 1H), 5.12 (dd, J = 10.8, 1.5 Hz, 1H), 4.90 (d, J = 6.4 Hz, 1H), 4.83 (t, J = 5.5 Hz, 1H), 4.69 (s, 1H), 3.80- 3.52 (m, 4H), 0.79 (s, 3H); MS (ES +): 307.1

45 (M + H) +; HPLC purity: 98.9% (270 nm, t R = 10.6 min .; solvent A: 0.1 M amino acetate, solvent B: acetonitrile; 0-5 min., 0% B; 5-15 min ., 0-45% B; 15-20 min., 45-90% B; 20-25 min., 90-0% B.); IR (net): 3323, 1621, 1592, 1377 cm-1. Anal. calc. for C14H18N4O8 • 0.5 H2O • 0.5 MeOH: C, 52.56; H, 6.39; N, 16.91. Found: C, 52.51; H, 6.00; N, 16.61.

50 Example 5

7 - ((2S, 3R, 4R, 5R) -3,4-Dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2,4] triazin- 4 (3H) -one 55 (5).

A solution of 2b (300 mg, 0.54 mmol, was treated, its preparation is described in example 2) in MeOH (40 ml) with 1 N HCl (aq. 1.85 ml) and Pd / C (10% , 150 mg) followed by hydrogenation (60 psi) (414 kPa) for 18 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 1: 1) to give 5 (48 mg, 32%, Rf = 0.66, chloroform / CMA 80 = 1: 1 ) as a yellow solid (a mixture of two diastereoisomers, ratio = 2: 1). 1H-NMR (DMSO-d6): 5 11.61 (sa, 1H), 7.84 (s) & 7.81

(s) (1H), 6.852 (d, J = 4.3 Hz) & 6.846 (d, J = 4.3 Hz) (1H), 6.65 (d, J = 4.3 Hz) & 6, 63 (d, J = 4.3 Hz) (1H), 5.28 (s) & 5.23 (s) (1H), 4.96 (d, J = 6.6 Hz) & 4.93 ( d, J = 6.6 Hz) (1H), 4.83-4.62 (m, 2H), 3.86-3.50 (m, 4H), 1.09 (s) & 0.79

10 (s) (3H); MS (ES-): 280.4 (MH) -. Anal. calc. for C12H15N3O5 • 1.75 H2O: C, 46.08; H, 5.96; N, 13.43; Found: C, 45.91; H, 5.54; N, 13.21.

Example 6

4-Amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2, 4] triazin-5carboxamide (6g).

to.

 A solution of 3a (27.85 g, 44.23 mmol, preparation given according to example 3) in pyridine (400 ml) was treated with 4-methoxytriphenylmethyl chloride (56.74 g, 178.24 mmol) followed by stirring at 70 ° C for 16 h. The reaction mixture was diluted with EtOAc (1.5 L) and washed with water (2 x 700 ml) and brine (500 ml), dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 4: 1) to give 6a (28.38 g, 71%, Rf = 0.49, hexanes / EtOAc = 4: 1 ) as a light yellow solid. 1H-NMR (DMSO-d6): 5 7.91 (s, 1H), 7.63 (s, 1H), 7.45-7.12 (m, 27H), 6.96 (s, 1H), 6.87 (d, J = 8.9 Hz, 2H), 5.56 (s, 1H), 4.74-4.50 (m, 6H), 4.20-4.12 (m, 1H) , 4.02 (d, J = 8.5 Hz, 1H), 3.87-3.64 (m, 2H), 3.71 (s, 3H), 1.05 (s, 3H).

b.

A solution of 6a (26.1 g, 28.94 mmol) in DME (500 ml) was treated with potassium vinyltrifluoroborate (7.2 g, 53.75 mmol), NaHCO3 (7.2 g, 85.70 mmol ), Pd (PPH3) 2Cl2 (1.4 g, 98%, 1.99 mmol) and H2O (65 ml) followed by reflux for 6 h. The reaction mixture was treated with water (500 ml) and extracted with EtOAc (1.8 L and 0.5 L). The combined extracts were washed with brine (500 ml) and dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 6: 1) to give 6b (18.3 g, 74%, Rf = 0.39) as a light yellow solid. 1H-NMR (DMSO-d6): 7.56 (s, 1H), 7.44-7.12 (m, 28H), 7.01 (dd, J = 17.2, 11.0 Hz, 1H ), 6.93 (s, 1H), 6.84 (d, J = 8.8 Hz, 2H), 5.57 (s, 1H), 5.31 (d, J = 17.2 Hz, 1H ), 5.16 (d, J = 11.0 Hz, 1H), 4.76-4.52 (m, 6H), 4.22-4.13 (m, 1H), 4.04 (d, J = 8.4 Hz, 1H), 3.88-3.70 (m, 2H), 3.71 (s, 3H), 1.05 (s, 3H); MS (ES +): 849.5 (M + H) +.

C.

A solution of 6b (8 g, 9.42 mmol) in dichloromethane (250 ml) and MeOH (40 ml) was cooled to -78 ° C and bubbled with O3 until a blue color appeared. The reaction mixture was treated with NaBH4 (1.8 g, 46.63 mmol) at 78 ° C, heated and stirred at RT for 19 h. It was then neutralized with HOAc followed by concentration to remove most of the solvent. The residue was treated with EtOAc (500 ml) and washed with water (2 x 400 ml). The aqueous phase was extracted again with EtOAc (300 ml). The combined organic extracts were washed with brine (500 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 3: 1) to give 6c (3.987 g, 50%, Rf = 0.46) as a white solid. 1H-NMR (DMSO-d6): 5 9.77 (s, 1H), 7.49 (s, 1H), 7.40-7.12 (m, 27H), 6.81 (d, J = 9 , 0 Hz, 2H), 6.66 (s, 1H), 6.27 (t, J = 5.0 Hz, 1H), 5.57 (s, 1H), 4.74-4.50 (m , 8H), 4.20-4.12 (m, 1H), 4.01 (d, J = 8.4 Hz, 1H), 3.86-3.66 (m, 2H), 3.70 ( s, 3H), 1.06 (s, 3H); MS (ES +): 853.2 (M + H) +.

d.

A solution of 6c (717 mg, 0.84 mmol) in dichloromethane (40 ml) was treated with Dess-Martin reagent (15%, w / w, 2.8 ml, 1.33 mmol) followed by stirring at RT for 4 h. The reaction mixture was diluted with EtOAc (20 ml), treated with a little MgSO4, concentrated and purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 3: 1) to give 6d (621 mg, 87%, Rf = 0.48) as a white solid. 1H-NMR (DMSO-d6): 5 10.89 (s, 1H), 9.28 (s, 1H), 7.84 (s, 1H), 7.47 (s, 1H), 7.44- 7.10 (m, 27H), 6.84 (d, J = 8.9 Hz, 2H), 5.56 (s, 1H), 4,764.50 (m, 6H), 4.24-4.14 (m, 1H), 4.06 (d, J = 8.3 Hz, 1H), 3.90-3.70 (m, 2H), 3.71 (s, 3H), 1.09 (s, 3H).

and.

A solution of 6d (220 mg, 0.26 mmol) in 1,4-dioxane (3.4 ml) was treated with water (1.0 ml) and then hydroxylamine-O-sulfonic acid (106 mg, 97%, 0.91 mmol) followed by stirring at RT for 45 min. Additional hydroxylamine-O-sulfonic acid (318 mg, 97%, 2.73 mmol) was added and stirring was continued for 2 h. The reaction mixture was cooled with ice / water and reacted with a cold suspension of KOH (7.09 mmol) in water (2 ml) and 1,4-dioxane (2 ml) followed by stirring at RT for 2 h . It was diluted with EtOAc (100 ml) and washed with water (60 ml). The aqueous phase was extracted again with EtOAc (80 ml). The combined extracts were washed with water (60 ml) and brine (500 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 2: 1) to give 6e (86 mg, 57%, Rf = 0.25, hexanes / EtOAc = 2: 1) as a light brown gel. 1H-NMR (DMSO-d6): 5.8.13 (s, 1H), 7.45-7.25 (m, 16H), 5.63 (s, 1H), 4.74 (s, 2H), 4.68-4.53 (m, 4H), 4.25-4.17 (m, 1H), 4.04 (d, J = 8.5 Hz, 1H), 3.91-3.70 ( m, 2H), 1.06 (s, 3H); MS (ES +): 598.1 (M + Na) +.

F.

A solution of 6e (20 mg, 0.035 mmol) in EtOH (6 ml) was treated with conc. NH4OH. (28-30%, 1.8 ml) and then H2O2 was added dropwise (30% in H2O, 0.011 ml was taken and added to 0.2 ml of EtOH) followed by stirring at RT for 18 h. The reaction mixture was concentrated and purified by silica gel column chromatography (hexanes / EtOAc, 1: 0 to 1: 1, then hexanes / EtOAc / MeOH 1: 1: 0.1) to give 6f (12 mg , 58%, Rf = 0.36, hexanes / EtOAc / MeOH = 1: 1: 0.1) as a white solid. 1H-NMR (MeOH-d4): 5.87 (s, 1H), 7.40-7.00 (m, 16H), 5.70 (s, 1H), 4.75-4.42 (m , 6H), 4.26-4.18 (m, 1H), 3.90 (d, J = 8.0 Hz, 1H), 3.82-3.64 (m, 2H), 1.04 ( s, 3H); MS (ES +) MS (ES +): 594.1 (M + H) +.

g.

A solution of 6f (10 mg, 0.017 mmol) in MeOH (15 ml) was treated with 1 N HCl (aq., 0.69 ml) and Pd / C (10%, 50 mg) followed by hydrogenation (60 psi ) (414 kPa) for 15 h. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 0: 1, then CMA 80 / CMA 50 1: 1, Rf = 0.55, CMA 80 / CMA 50 = 1 : 1) followed by HPLC purification (CH3CN / H2O, 0-40 min., 035% CH3CN, 244 nm monitoring) and column purification again on silica gel (CMA 80 / CMA 50, from 1: 0 to 1: 1) giving 6g (3.3 mg, colorless film, 60%). 1H-NMR (MeOH-d4): 8.06 (s, 2H), 7.89 (s, 1H), 7.30 (s, 1H), 5.57 (s, 1H), 4.02- 3.80 (m, 4H), 0.99 (s, 3H); MS (ES +): 324.2 (M + H) +; IR (net): 3550, 3020, 2917, 1674, 1334 cm-1.

Example 7

(2S, 3R, 4R, 5R) -2- (4-Amino-5- (hydroxymethyl) pyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) - 3-methyltetrahydrofuran-3,4-diol (7).

A solution of 6c (120 mg, 0.14 mmol, preparation given according to example 6) in MeOH (15 ml) was treated with 1 N HCl (aq. 0.69 ml) and Pd / C (10%, 50 mg) followed by hydrogenation (60 psi) (414 kPa) for 24 h. The reaction mixture was filtered and concentrated. The residue was treated with acetonitrile (15 ml) and 1 N HCl (aq. 1.5 ml) followed by stirring at RT for 16 h. It was then concentrated to dryness and purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 0: 1) to give 7 (17 mg, 39%, Rf = 0.33, CMA 80) as a

15 yellow oil 1H-NMR (DMSO-d6, D2O exchange): 5.80 (s, 1H), 6.63 (s, 1H), 5.37 (s, 1H), 4.69 (s, 2H), 3.843 , 40 (m, 4H), 0.81 (s, 3H); MS (ES +): 311.1 (M + H) +.

Example 8

(2S, 3R, 4R, 5R) -2- (4-Amino-5-fluoropyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran -3.4diol (8f).

A solution of 2b (200 mg, 0.36 mmol, preparation given according to example 2) in dichloromethane (16 ml) was cooled with ice / water and treated with NBS (65 mg, 0.36 mmol) in several portions followed by agitation at TA

5 for 22 h. The reaction mixture was concentrated and purified by silica gel column chromatography (hexanes / EtOAc, 1: 0 to 1: 1, Rf = 0.58, hexanes / EtOAc = 1: 1) to give 8a (155 mg, colorless oil, 68%). 1 H-NMR (DMSO-d6): 11.79 (s, 1 H), 7.92 (s, 1 H), 7.44-7.20 (m, 15 H), 6.79 (s, 1 H), 5.53 (s, 1H), 4.77-4.50 (m, 6H), 4.22-4.14 (m, 1H), 4.01 (d, J = 8.9 Hz, 1H) , 3.90-3.66 (m, 2H), 1.08 (s, 3H); MS (ES-): 628.5 (M-H) -.

10 b. A solution of 8a (2.42 g, 3.84 mmol) in POCl3 (40 ml) was stirred at 80 ° C for 4 h and concentrated to dryness. The residue was treated with chloroform (300 ml) and washed with 1 M NaHCO3 (150 ml), water (150 ml), brine (100 ml), and dried over MgSO4. After filtration and concentration, the residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 8: 1, Rf = 0.53, hexanes / EtOAc = 6: 1) to give 8b (1 , 68 g, 68%) as a yellow syrup. MS (ES +): 670.2 (M + Na) +.

C. A solution of 8b (2.2 g, 3.39 mmol) in THF (24 ml) was cooled to -78 ° C and treated with n-BuLi dropwise (2.5 M in hexane, 2.95 ml, 7 , 38 mmol). The reaction mixture was stirred at -78 ° C for 0.5 h and treated with trimethyltin chloride dropwise (1 M in THF, 3.4 ml, 3.4 mmol) at -78 ° C followed by heating to RT and stirring at TA for 19 h. Then it was treated with NH4Cl sat. (ac. 200 ml) and extracted with EtOAc (2 x 200 ml). They washed

20 extracts combined with brine (150 ml), dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 6: 1, Rf = 0.59, hexanes / EtOAc = 6: 1) to give 8c (386 mg, not yet pure, used as is for the next stage) as a yellow oil. MS (ES +): 733.4 (M + H) +.

25 d. A solution of the above product 8c (351 mg) in acetonitrile (7 ml) was treated with Selectfluor ™ (180 mg, 95%, 0.48 mmol) followed by stirring at RT for 17 h. The reaction mixture was filtered, the filtrate was concentrated and the residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 6: 1, Rf = 0.25, hexanes / EtOAc = 6: 1) giving 8d (120 mg, used as is for the next stage) as a yellow oil. MS (ES +): 610.0 (M + Na) +.

30 e. A solution of the previous product 8d (114 mg) in EtOH (3 ml) and chloroform (0.75 ml) was treated with triethylamine (0.57 ml, 4.09 mmol) and then with methoxylamine hydrochloride (172 mg, 98 %, 2.20 mmol) followed by stirring at 50 ° C for 14 h. The reaction mixture was concentrated and purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 2: 1, Rf = 0.42, hexanes / EtOAc = 2: 1) to give 8e (13, 5 mg, used as is for the

35 next stage) as a colorless film. MS (ES +): 599.1 (M + H) +.

F. A solution of the above product 8e (6.5 mg) in MeOH (10 ml) was treated with 1 N HCl (0.46 ml aq.) And Pd / C (10%, 35 mg) followed by hydrogenation (60 psi ) (414 kPa) for 22 h. The reaction mixture was filtered, concentrated and purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 0: 1, Rf =

5 0.39, CMA 80) followed by HPLC purification (CH3CN / H2O, 0-40 min., 0-35% CH3CN, monitoring at 244 nm) and column purification again (chloroform / CMA 80, of 1: 0 to 0: 1) giving 8f (2.0 mg, 0.5% for 4 stages) as a white solid. 1H-NMR (MeOH-d4): 5.70 (s, 1H), 6.62 (s, 1H), 5.55 (s, 1H), 4.00-3.60 (m, 4H), 0.97 (s, 3 H); 19F-NMR (MeOH-d4): 5-160.93 (s, 1F); MS (ES +): 299.1 (M + H) +; IR (net): 3296, 2919, 1620, 1530 cm

. 10

Example 9

4-Amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2 , 4] triazin-5carbonitrile (9d).

20 a. A solution of 4e (2 g, 2.32 mmol, preparation given in example 4) in dichloromethane (60 ml) and MeOH (9.6 ml) was cooled to -78 ° C and bubbled with O3 until a blue color appeared . The reaction mixture was treated with NaBH4 (440 mg, 11.40 mmol) at -78 ° C, heated and stirred at RT for 20 h. Additional NaBH4 (500 mg, 12.95 mmol) was added and stirring was continued at RT for 1 h. The reaction mixture was neutralized with HOAc followed by concentration to remove most of the solvent. The residue was treated with EtOAc (300 ml) and washed

25 with water (2 x 150 ml) and brine (100 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 3: 1) to give 9a (529 mg, 26%, Rf = 0.49, hexanes / EtOAc = 1: 0) as a white solid 1H-NMR (DMSO-d6): 5.9.80 (s, 1H), 7.50-7.12 (m, 28H), 6.82 (d, J = 8.9 Hz, 2H), 6, 49 (s, 1H), 6.31 (t, J = 5.1 Hz, 1H), 5.5 0 (s, 1H), 4.81 (d, J = 5.1 Hz, 2H), 4 , 22 (d, J = 3.0 Hz, 1H), 4.16-4.08 (m, 1H), 3.70 (s, 3H), 3.32-3.12 (m, 2H), 1.47 (s, 3H), 1.26 (s, 3H), 1.09 (9s, 3H); MS (ES-): 863.2 (M-H) -.

b. A solution of 9a (487 mg, 0.56 mmol) in dichloromethane (25 ml) was treated with Dess-Martin reagent (15%, w / w, 1.9 ml, 0.9 mmol) followed by stirring at RT for 3 h. The reaction mixture was diluted with EtOAc (10 ml), treated with a little MgSO4 and silica gel followed by concentration and column purification (hexanes / EtOAc, of

1: 0 to 3: 1) giving 9b (448 mg, 93%, Rf = 0.64) as a white solid. 1 H-NMR (DMSO-d6): 5 10.96 (s, 1 H), 9.73 (s,

1H), 7.82 (s, 1H), 7.50-7.16 (m, 28H), 6.85 (d, J = 8.9Hz, 2H), 5.48 (s, 1H), 4 , 26 (d, J = 2.8 Hz, 1H), 4.22-4.14 (m, 1H), 3.71 (s, 3H), 3.34-3.16 (m, 2H), 1.49 (s, 3H), 1.28 (s, 3H), 1.08 (s, 3H).

C. A solution of 9b (244 mg, 0.28 mmol) in 1,4-dioxane (4.4 ml) was treated with water (1.1 ml) and then acid

Hydroxylamine-O-sulfonic acid (460 mg, 97%, 3.95 mmol) followed by stirring at RT for 1.5 h. Additional hydroxylamine-O-sulfonic acid (230 mg, 97%, 1.97 mmol) was added and stirring was continued for 2 h. The reaction mixture was cooled with ice / water and slowly treated with a cold suspension of KOH (11.51 mmol) in water (3 ml) and 1,4-dioxane (3 ml) followed by stirring at RT for 2 h . It was diluted with EtOAc (100 ml), washed with water (60 ml). The aqueous phase was extracted again with EtOAc (80 ml). The combined extracts were washed with water

10 (60 ml) and brine (60 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 2: 1) to give 9c (76 mg, 46%, Rf = 0.29, hexanes / EtOAc = 2: 1) as a transparent oil 1H-NMR (DMSO-d6): 5.8.10 (s, 1H), 7.50-7.74 (m, 15H), 7.00 (s, 1H), 5.51 (s, 1H), 4.28-4.12 (m, 2H), 3.34-3.12 (m, 2H), 1.53 (s, 3H), 1.30 (s, 3H), 1.00 (s, 3H); MS (ES-): 586.1 (M-H) -.

15 d. A solution of 9c (63 mg, 0.11 mmol) in acetonitrile (12 ml) was treated with 1 N HCl (aq, 1.2 ml) followed by stirring at RT for 19 h. The reaction mixture was concentrated and purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 0: 1, Rf = 0.50, CMA 80) to give 9d (26 mg, 77%) Like a white solid 1H-NMR (DMSO-d6): 5.122 (s, 1H), 7.36 (s, 1H), 5.36 (s, 1H), 4.97 (d, J = 6.7 Hz, 1H), 4.89 (t, J = 5.2 Hz,

1H), 4.83 (s, 1H), 3.82-3.56 (m, 4H), 0.81 (s, 3H); MS (ES +): 328.1 (M + Na) +; HPLC purity: 99.5% (270 nm, t R = 9.7 min .; solvent A: 0.1 M ammonium acetate, solvent B: acetonitrile; 0-5 min., 0% B; 5-15 min., 0-45% of B; 15-20 min., 45-90% of B; 20-25 min., 90-0% of B); IR (pure): 3374.3257, 2215, 1657, 1517, 1034 cm -1.

Example 10

4-Amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2, 4] triazin-5carboximidamide (10b).

A solution of 6e (31 mg, 0.054 mmol, preparation given in example 6) in EtOH (5 ml) was treated with NH2OH (50% in H2O, 0.5 ml, 8.16 mmol) followed by reflux for 1 h and concentration giving 10a, MS (ES-): 35 607.6 (MH) -. The residue was dissolved in EtOH (15 ml), treated with HOAc (1.5 ml) and a small amount of Raney nickel followed by hydrogenation (60 psi) (414 kPa) for 21 h. The reaction mixture was filtered and concentrated. Be

The residue was dissolved in MeOH (15 ml) and treated with 1 N HCl (aq. 0.92 ml) and Pd / C (10%, 60 mg) followed by hydrogenation (60 psi) (414 kPa) for 22 h. The reaction mixture was filtered and concentrated. The residue was purified twice by silica gel column chromatography (CMA 80 / CMA 50, from 1: 0 to 1: 1, Rf = 0.28, CMA 80 / CMA 50 = 1: 1) to give 10b (5 , 7 mg, 33%) as a light brown film. 1H-NMR (MeOH-d4): 5 7.96 (s, 1H), 7.20 (s, 1H), 5.50 (s, 1H), 3.92-3.66 (m, 4H), 0.88 (s, 3 H). MS (ES +): 323.1 (M + H) +.

Example 11

4-Amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2, 4] methyl triazine-5-carboxylate (11c)

to. A solution of 6d (200 mg, 0.24 mmol, was treated, its preparation is described in example 6) in acetonitrile (5.4 ml) and t-BuOH (1.8 ml) with water (1.0 ml) and cooled to about 8 ° C. The cooled solution was treated with 2-methyl-2-butene (0.2 ml, 1.89 mmol), NaH2PO4 (48 mg, 0.4 mmol) and NaClO2 (240 mg, 80%, 2.12 mmol) followed by stirring at RT for 23 h. Additional NaClO2 (240 mg, 80%, 2.12 mmol) was added and stirring was continued at RT for 42 h. The reaction mixture was diluted with ether (200 ml) and washed with water (50 ml). The aqueous phase was extracted with ether (100 ml) again. The combined extracts were washed with brine (50 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc / MeOH, from 3: 1: 0 to 3: 1: 0.08) to give 11a (60 mg, 29%, Rf = 0.43, hexanes / EtOAc / MeOH = 3: 1: 0.08) as a clear oil. 1H-NMR (DMSO-d6): 5.70 (s, 1H), 7.62 (s, 1H), 7.44-7.14 (m, 28H), 6.83 (d, J =

25 9.0 Hz, 2H), 5.58 (s, 1H), 4.74-4.52 (m, 6H), 4.20-4.10 (m, 1H), 3.99 (1H) , 3.84-3.64 (m, 2H), 3.70 (s, 3H), 1.06 (s, 3H).

b. A solution of 11a (50 mg, 0.058 mmol) in DMF (2 ml) was treated with MeOH (0.05 ml, 1.23 mmol), DMAP (14 mg, 0.113 mmol) and N- (3-dimethylaminopropyl hydrochloride) ) -N'-ethylcarbodiimide (240 mg, 125 mmol) followed by

30 stirring at RT for 16 h. The reaction mixture was diluted with EtOAc (120 ml), washed with water (2 x 60 ml) and brine (60 ml), dried over MgSO4, filtered and concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 4: 1) to give 11b (20 mg, 39%, Rf = 0.48, hexanes / EtOAc = 4: 1) as a transparent oil 1H-NMR (CHCl3-d): 11.45 (s, 1H), 7.86 (s, 1H), 7.44-7.04 (m, 28H), 6.83 (d, J = 8 , 8 Hz, 2H), 5.78 (s, 1H), 4.90-4.46 (m, 6H), 4.44-4.32 (m, 1H), 4.08 (d, J = 8.7 Hz, 1H), 3.96-3.60 (m, 2H), 3.80 (s, 3H), 3.75 (s, 3H), 1.12 (s, 3H).

5 c. A solution of 11b (20 mg, 0.023 mmol) in MeOH (10 ml) and EtOAc (5 ml) was treated with 1 N HCl (aq. 0.69 ml) and Pd / C (10%, 50 mg) followed by hydrogenation at 60 psi (414 kPa) for 23 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 1: 1, Rf = 0.23, chloroform / CMA 80 = 1: 1) to give 11c (3.1 mg, light brown solid, 40%). 1H-NMR (MeOH-d4): 5 7.94 (s, 1H), 7.34 (s, 1H), 5.56 (s, 1H), 4.00-3.70 (m, 4H), 3.92 (s, 3H), 0.97 (s, 3H); MS (ES +): 337.9 10 (M-H) -.

Example 12

4-Amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2f] [1,2,4 ] triazin-5-carboxylic (12)

A solution of 11a (77 mg, 0.089 mmol, its preparation is described in example 11) in MeOH (15 ml) was treated with 1 N HCl (aq. 0.69 ml) and Pd / C (10% , 50 mg) followed by hydrogenation at 60 psi (414 kPa) for 29 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was treated with water (50 ml) and washed with EtOAc (2 x 25 ml). The aqueous phase was concentrated to dryness and the desired product (12, 12 mg, 42%, yellow solid) crystallized from MeOH / EtOAc. 1H-NMR (DMSO-d6): 5 13.28 (s, 1H), 9.59 (s, 1H), 8.49 (s, 1H), 8.07 (s, 1H), 7.30 ( s, 1H), 5.37 (s, 1H), 4.10-3.50 (m, 4H), 0.81 (s, 3H); MS (ES +): 325.0 (M + H) +.

Example 13

(2S, 3R, 4R, 5R) -2- (4-Amino-5- (1,2-dihydroxyethyl) pyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran-3,4-diol (13b)

to. A solution of 4e (500 mg, 0.58 mmol, was treated, its preparation is described in example 4) in acetone / water (9: 1, 10 ml) with 4-methylmorpholine N-oxide (140 mg, 97% , 1.16 mmol) and then osmium tetroxide (4% w / v in 5 water, 0.15 ml, 0.024 mmol) followed by stirring at RT for 12 h. The reaction mixture was diluted with water (10 ml) and concentrated to remove only acetone. The aqueous residue was treated with EtOAc (200 ml), washed with water (2 x 100 ml) and brine (100 ml), dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (hexanes / EtOAc, from 1: 0 to 2: 1) to give 13a (287 mg, a mixture of diastereoisomers, ratio = 1.1 / 1.0, 55%, Rf = 0.46, hexanes / EtOAc = 2: 1) as a clear oil. 1 H-NMR

10 (DMSO-d6): 5 10.02 (s) & 9.95 (s) (1H), 7.28-6.88 (m, 28H), 6.60 (d, J = 8.9 Hz , 2H), 6.46 (d, J = 3.5 Hz) & 6.39 (d, J = 3.8 Hz) (1H), 6.32 (d, J = 1.3 Hz, 1H) , 5.30 (s, 1H), 4.73-4.61 (m, 2H), 4.02 (d, J = 3.0 Hz) & 4.00 (d, J = 3.0 Hz) (1H), 3.93-3.86 (m, 1H), 3.49 (s, 3H), 3.48-3.31 (m, 2H), 3.05-2.91 (m, 2H ), 1.26 (s, 3H), 1.05 (s, 3H), 0.91 (s) & 0.89

(s) (3H); MS (ES-): 895.3 (M + H) +.

15 b. A solution of 13a (120 mg, 0.13 mmol) in acetonitrile (14 ml) was treated with 1 N HCl (aq, 1.4 ml) followed by stirring at RT for 20 h. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (chloroform / CMA 80, from 1: 0 to 0: 1, then CMA80 / CMA 50 1: 1, Rf = 0.40, CMA 80 / CMA 50 = 1: 1) giving 13b (11 mg, a mixture of diastereoisomers, yellow solid, 25%). 1H-NMR (MeOH-d4): D 7.77 (s, 1H), 6.75 (s) & 6.74 (s) (1H), 5.55 (s) & 5.54 (s) ( 1H), 5.02-4.90 (m, 1H), 4.00-3.58 (m, 6H), 0.95 (s, 3H); MS (ES +): 341.1

20 (M + H) +.

Example 14

Tetrahydrogenotriphosphate ((2R, 3R, 4R, 5S) -5- (4-aminopyrrolo [1,2-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy-4-methyltetrahydrofuran-2- il) methyl (14d).

to. A suspension of 1k HCl salt (300 mg, 0.95 mmol) in pyridine (9 ml) was treated with DMAP (99%, 30 mg, 0.24 mmol) and MMTrCl (97%, 460 mg, 1.44 mmol) followed by stirring at RT for 15 h. the mixture was diluted

5 reaction with chloroform (150 ml), washed with water (2 x 60 ml) and dried over MgSO4. After filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (hexanes / ethyl acetate, from 1: 0 to 1: 1, then chloroform / CMA 80, from 1: 0 to 2: 1 ) giving 539 mg of 14a (Rf = 0.29, chloroform / CMA 80 = 2/1) as a white solid. It was pure enough to be used for the next stage. MS (ES +): 575.3 (M + Na) +.

b. A solution of the previous 14a (300 mg) in pyridine (20 ml) was treated with DMAP (99%, 35 mg, 0.28 mmol) and 4-nitrobenzoyl chloride (520 mg, 98%, 2.75 mmol) followed by stirring at 70 ° C for 14 h. The reaction mixture was diluted with EtOAc (200 ml), washed with water (2 x 100 ml) and brine (75 ml), dried over MgSO4. Behind the

filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (hexanes / ethyl acetate, from 1: 0 to 1: 1) to give 14b (Rf = 0.77, hexanes / ethyl acetate = 1 / 1, 312 mg, 59% for two stages, yellow solid). 1H-NMR (DMSO-d6): 8.44-6.88 (m, 30H), 6.06 (sa, 1H), 5.81 (d, J = 3.9 Hz, 1H), 4, 50-4.40 (m, 1H), 3.75 (s, 3H), 3.55-3.48 (m, 2H), 1.56 (s, 3H); MS (ES-): 998.8 (M-1).

C.

 A solution of 14b (276 mg, 0.28 mmol) in CH3CN (28 ml) was treated with 0.2 N HCl (aq, 1.4 ml) followed by stirring at RT for 2.5 h. The reaction mixture was neutralized with 0.5 N NaOH (aq.) To pH = 5 followed by the addition of water (40 ml) and concentration in vacuo to remove only CH3CN. The aqueous residue was extracted with a mixture of CHCl3 / MeOH (5: 1, 100 ml, 50 ml). The combined organic extracts were dried over MgSO4. After filtration and concentration of the filtrate, the residue was purified by silica gel column chromatography (hexanes / ethyl acetate, 1: 0 to 1: 1) to give 14c (Rf = 0.58, hexanes / ethyl acetate = 1/1, 150 mg, 74%) as a yellow solid. 1H-NMR (DMSO-d6): 8.81-7.80 (m, 14H), 7.32 (sa, 1H), 7.12 (sa, 1H), 6.02 (sa, 1H), 5 , 73 (d, J = 3.4 Hz, 1H), 5.26 (t, 1H), 4.32-4.25 (m, 1H), 3.90-3.80 (m, 2H), 1.52 (s, 3 H); MS (ES +): 728.2 (M + H) +. Anal. calc. for C33H25N7O13 • 0.25 EtOAc: C, 54.48; H, 3.63; N, 13.08. Found: C, 54.72; H, 3.84; N, 12.71.

d.

 A suspension of 14c (50 mg, 0.069 mmol) in a mixture of pyridine (70 = 1) and dioxane (210 = 1) was treated with a freshly prepared solution of chloro-4H-1,3,2-benzodioxaphosforin-4- one (1 M in dioxane, 80 = 1). The reaction mixture was stirred at room temperature for 20 min. followed by treatment with a solution of tetrabutylammonium pyrophosphate (1.6 Bu3N · 1.0 H4P2O7, 50 mg, 0.11 mmol) in DMF (220 = 1) and tri-n-butylamine (70 = 1) simultaneously. The clear solution formed was stirred at room temperature for 30 min. followed by treatment with 2.9 ml of 1% I2 in Py / H2O (98/2). Excess iodine was reduced by 5% aqueous sodium thiosulfate (200 = 1) and the resulting solution was concentrated to dryness. The residue was treated with conc. NH4OH. (15 ml) and stirred at room temperature overnight followed by concentration to dryness. The residue was dissolved in H2O (20 ml) and washed with CH2Cl2 (2 x 15 ml). The aqueous phase was concentrated in vacuo for a short period of time to remove traces of CH2Cl2 and purified by DEAE ion exchange column chromatography with a linear gradient of TEAB buffer (1 M TEAB buffer, pH = 8.0 / H2O, from 0: 1 to 1: 0, total: 500 ml). Fractions containing the desired nucleotide were combined and concentrated. The residue was redissolved in H2O and further purified by HPLC (0.1 M CH3CN / TEAB buffer, pH = 8.0, 0-20 min., 0-35% CH3CN; 244 nm monitoring) giving 14d (tR = 17.00 min.). Fractions containing 14d were concentrated and redissolved in 3 ml of H2O and the concentration of 14d was measured to be 4.1 mM (yield: 18%) by UV (244 nm, ε = 35,000 M-1 cm -1) . 1H-NMR (D2O): 5 7.77 (sa, 1H), 6.93 (d, J = 4.0 Hz, 1H), 6.85 (d, 1H), 5.45 (s, 1H) , 4.34-4.10 (m, 2H), 4.10-3.96 (m, 2H), 0.78 (s, 3H); 31P-NMR (D2O): 5 -9.25 (d, J = 17.8 Hz, 1P), -9.78 (d, J = 17.9 Hz, 1P), -21.70 (m, 1P ); MS (ES-): 519.1 (M-1).

Example 15

The following illustrates representative pharmaceutical dosage forms, which contain a compound of formula I, or a pharmaceutically acceptable salt thereof ("compound X"), for prophylactic or therapeutic use in beings. The above formulations can be obtained by conventional procedures well known in the art. pharmaceutical art.

humans.

(i) Tablet 1

mg / tablet

Compound X =

100.0

Lactose

77.5

Povidone

15.0

Croscarmellose sodium

12.0

Microcrystalline cellulose

92.5

Magnesium stearate

3.0

300.0

(ii) Tablet 2

mg / tablet

Compound X =

20.0

Microcrystalline cellulose

410.0

Starch

50.0

Sodium Starch Glycolate

15.0

Magnesium stearate

5.0

500.0

(iii) Capsule

mg / capsule

Compound X =

10.0

Colloidal Silicon Dioxide

1.5

Lactose

465.5

Pregelatinized starch

120.0

Magnesium stearate

3.0

600.0

(iv) Injection 1 (1 mg / ml)

mg / ml

Compound X = (free acid form)

1.0

Dibasic sodium phosphate

12.0

Monobasic Sodium Phosphate 0.7

4,5

Sodium chloride

1.0 N sodium hydroxide solution (pH adjustment to 7.0-7.5)

c.s.

Water for

c.s. up to 1 ml

(v) Injection 2 (10 mg / ml)

mg / ml

Compound X = (free acid form)

10.0

Monobasic Sodium Phosphate 0.3

1.1

Dibasic sodium phosphate

Polyethylene Glycol 400

200.0

0.1 N sodium hydroxide solution (pH adjustment to 7.0-7.5)

c.s.

WFI

c.s. up to 1 ml

(vi) Spray

mg / pot

Compound X = Oleic Acid

20.0 10.0

Trichloromonofluoromethane

5,000.0

Dichlorodifluoromethane

10,000.0

Dichlorotetrafluoroethane

5,000.0

Claims (13)

1. Compound of formula I: in which: R is ORa, SRa, NRaRb, NRaNRbRc, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl 10 substituted, aryl, substituted aryl, (CH2) n-CH (NHR3) CO2Rb, (CH2) nS-alkyl, (CH2) nS-aryl, Cl, F, Br, I, CN, COORa, CONRaRb, NHC (= NRa) NHRb, NRaORb, NRaNO, NHCONHRa, NRaN = NRb, NRaN = CHRb, NRaC (O) NRbRc, NRaC (S) NRbRc, NRaC (O) ORb, CH = N-ORa, NRaC (= NH) NRbRc, NRaC (O) NRbNRcRd, OC (O) Ra, OC (O) -ORa, ONHC (O) O-alkyl, ONH-C (O) O-aryl, ONRaRb, SNRaRb, S-ONRaRb, CHO, C (= S ) NRaRb, nitro, C (= NRa) ORb or SO2NRaRb; and R3 is H, CN, NO2, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, alkynyl 15 substituted, CH = CF2, CH (= NRa) ORb, CHO, CH = CH-OCH3, NHCONH2, NHCSNH2, CONRaRb, CSNRaRb, CO2Ra, alkoxy, NH2, alkylamino, dialkylamino, halogen, (1,3-oxazol-2 -yl), (1,3-oxazol-5-yl), (1,3-thiazol-2-yl), (imidazol-2-yl), (2-oxo [1,3] dithiol-4-yl ), (furan-2-yl), (2H [1,2,3] triazol-4-yl), C (= NH) NH2, C (= NH) NHOH, C (= NOH) NH2, acyl, acyl substituted, ORa, C (= NRa) Rb, CH = NNRaRb, CH = NORa, CH (ORa) 2, B (ORa) 2, C = CC (= O) NRaRb, (CH2) nS-alkyl, (CH2) nS-aryl, (CH2) nS (O) -alkyl, (CH2) nS (O) -aryl, (CH2) nS (O2) -alkyl, (CH2) n S (O2) -aryl, (CH2) n-SO2NRaRb or (CH2) n-ORa; or R and R3 together with the atoms to which they bind can form a cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or substituted heteroaryl; n is 0-5; R1 is H, NRaRb, Cl, F, ORa, SRa, NHCORa, NHSO2Ra, NHCONHRa, CN, alkyl, aryl, ONRaRb or NRaC (O) ORb; R2 is a nucleoside sugar group; Ra, Rb, Rc and Rd are independently selected from the group consisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, heterocyclic, aryl, substituted aryl, acyl, substituted acyl, SO2- alkyl, amino, substituted amino and NO; or Ra and Rb together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino; or Rb and Rc together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino; 35 and Rc and Rd are independently selected from the group consisting of H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl and substituted heteroaryl; or Rc and Rd together with the N atom to which they bind can form a heterocycloalkyl, substituted heterocycloalkyl, heteroaryl or Substituted heteroaryl; or a pharmaceutically acceptable salt thereof, for use in the treatment of a viral infection in an animal. 2. A compound according to claim 1, wherein R is hydroxyl, chloro, methoxy, mercapto, amino, methylamino, isopropylamino, propylamino, ethylamino, dimethylamino, cyclopropylamino, 2-aminoethylamino, 1- (2-hydroxyethyl) hydrazino, hydrazino , 1-methylhydrazino, azetidino or pyrrolidino. 3. A compound according to any one of claims 1 to 2, wherein R1 is H or NRaRb. fifty 4. Compound according to any of claims 1 to 3, wherein R2 is selected from: 5. A compound according to any one of claims 1 to 3, wherein R2 is selected from: 6. Compound according to any of claims 1 to 3, wherein R2 is: 7. Compound according to any of claims 1 to 3, wherein R2 is selected from:

8.

Compound according to any one of claims 1 to 3, wherein R2 is:

9.

Compound according to any one of claims 1 to 3, wherein R2 is:

10.

Compound according to any one of claims 1 to 3, wherein R2 is ribose, 2-methylribose, 2-deoxyribose; 2-deoxy-2-fluororibose; arabinose; 2-deoxy-2-fluoroarabinous; 2,3-dideoxyiribose; 2,3-dideoxy-2-fluoroarabinous; 2,3-dideoxy-3-fluororibose; 2,3-dideoxy-2,3-dideshydroribribose; 2,3-dideoxy-3-azidorribose; 2.3

dideoxy-3-tiarribose; 2,3-dideoxy-3-oxarribose; tiorribosa; 2-deoxytriorribose; 2-deoxy-2-fluorothiorribose; thioarabinous; 2-deoxy-2-fluorothioarabinous; 2,3-dideoxytrioribose; 2,3-dideoxy-2-fluorothioarabinous; 2,3-dideoxy-3fluorotiorribose; 2,3-dideoxy-2,3-dideshydrotioribose; 2,3-dideoxy-3-azidothiorribose; 4-hydroxymethyl-cyclopent-2-ene; 2,3-dihydroxy-4-hydroxymethylcyclopent-4-ene; 3-hydroxy-4-hydroxymethylcyclopentane; 2-hydroxy-4-hydroxymethylcyclopentene; 5-Fluoro-3-hydroxy-4-hydroxymethylcyclopentane; 2,3-dihydroxy-4-hydroxymethyl-5-methylenecyclopentane; 4-hydroxymethylcyclopentane, 2,3-dihydroxy-4-hydroxymethylcyclopentane; 2,3-dihydroxymethylcyclobutane; 4-hydroxymethylpyrrolidine; 2,3-dihydroxy-4-hydroxymethylpyrrolidine; 2/3-hydroxy-4-hydroxymethylpyrrolidine; 2-fluoro-3-hydroxy-4hydroxymethylpyrrolidine; or 3-fluoro-2-hydroxy-4-hydroxymethyl-pyrrolidine. Compound according to any one of claims 1 to 10, wherein R 3 is CN, hydroxymethyl, 1,2-dihydroxyethyl, vinyl, aminocarbonyl, methoxycarbonyl, carboxyl, fluoro, bromine or C (= NH) NH 2. 12. Compound according to any of claims 1 to 11, wherein Ra, Rb, Rc and Rd are independently selected from the group consisting of H, alkyl and substituted alkyl; or Ra and Rb together with the nitrogen 15 to which they bind form a pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino ring; or Rb and Rc together with the nitrogen to which they bind form a ring of pyrrolidino, piperidino, piperazino, azetidino, morpholino or thiomorpholino. 13. Compound according to claim 1, which is a compound of the following formula or a pharmaceutically acceptable salt thereof; in which X is H or alkyl. 14. A compound according to claim 13, which is a compound of the following formula where R’7 is H or CH3 and X is H or CH3. 30 15. Compound according to claim 1, which is (2S, 3R, 4R, 5R) -2- (4-aminopyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5 (hydroxymethyl ) -3-methyltetrahydrofuran-3,4-diol; (2S, 3R, 4R, 5R) -2- (4- (dimethylamino) pyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran- 3,4-diol; 35 (2S, 3R, 4R, 5R) -2- (4-amino-5-bromopyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3- methyltetrahydrofuran-3,4-diol; (2S, 3R, 4R, 5R) -2- (4-amino-5-vinylpyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran -3,4-diol;  40 7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2,4] triazin -4 (3H) -one; 4-amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2, 4] triazine-5 carboxamide; (2S, 3R, 4R, 5R) -2- (4-amino-5- (hydroxymethyl) pyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) - 3-methyltetrahydrofuran-3,4diol; 5 (2S, 3R, 4R, 5R) -2- (4-amino-5-fluoropyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3- methyltetrahydrofuran-3,4-diol; 4-amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2, 4] triazine-5carbonitrile; 10 4-amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2 , 4] triazine-5carboximidamide; ((2R, 3R, 4R, 5S) -5- (4-aminopyrrolo [1,2-f] [1,2,4] triazin-7-yl) -3,4-dihydroxy-415 methyltetrahydrofuran-2 tetrahydrogen -yl) methyl; 4-amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2-f] [1,2, 4] methyl triazine-5-carboxylate; 4-Amino-7 - ((2S, 3R, 4R, 5R) -3,4-dihydroxy-5- (hydroxymethyl) -3-methyltetrahydrofuran-2-yl) pyrrolo [1,2f] [1,2, 4] triazine-5-carboxylic; or (2S, 3R, 4R, 5R) -2- (4-amino-5- (1,2-dihydroxyethyl) pyrrolo [1,2-f] [1,2,4] triazin-7-yl) -5- (hydroxymethyl) -3-methyltetrahydrofuran3,4-diol; 25 or a pharmaceutically acceptable salt thereof. 16. Compound according to any of claims 1 to 15, wherein the viral infection is selected from the group consisting of: hepatitis B, hepatitis C, human immunodeficiency virus, polio, Coxsackie virus A and B, 30 rhinovirus, echovirus, smallpox virus, Ebola virus and West Nile virus. 17. Compound according to claim 16, wherein the viral infection is HCV.